CN1125064C - 3-pyridyl enantiomers and their use as analgesics - Google Patents

Abstract

The present invention relates to a method of controlling pain in mammals, including humans, which comprises administering to a mammal or patient in need of such treatment a compound of formula or a pharmaceutically acceptable salt thereof. The invention also relates to selected (R) and (S) compounds of formula which are useful as analgesics, neuronal cell death inhibitors and anti-inflammatory agents.

Description

3-pyridyl enantiomer and its use as an analgesic

This application is a continuation-in-part of co-pending US Patent Application Serial No. 08/763,278, filed December 1,1996.

Field of the invention

The present invention relates to some (R) and (S)-enantiomers of a class of substituted 3-pyridyloxyalkyleneazetidin-2-yl compounds having appreciable activity as analgesics. Furthermore, some (R)-enantiomers possess surprisingly increased toxicity properties over the corresponding (S)-enantiomers of the same compound. In addition to having analgesic activity, the compounds are effective in preventing neuronal cell death and in treating or preventing inflammation.

Background of the invention

Finding stronger and more effective pain control agents or analgesics has been an important research goal of the medical community. A large number of diseases and conditions produce pain as part of the disease or condition. Relieving this pain is a major aspect of improving or treating the overall disease or condition. Pain and its possible allievation are also related to the mental and physical condition of the individual patient. One or a class of pain relievers may not be effective for a particular patient or group of patients, creating a need to find other compounds or drugs that are effective analgesics. Opioid and non-opioid drugs are the two main classes of analgesics (Dray, A. and Urban. L., Ann. Rev. Pharmacol. Toxicol., 36:253-280, 1996). Opioids such as morphine act on opioid receptors in the brain, thereby blocking the transmission of pain signals in the brain and spinal cord (Cherney, N.I., Drug, 51:713-737, 1996). Opioids such as morphine are easily abused and addictive. Non-opioids such as non-steroidal anti-inflammatory drugs (NSAIDs) generally (but not exclusively) block prostaglandin production to prevent the sensitization of nerve endings that facilitates the transmission of pain signals to the brain (Dray et al. , Trends inPharmacol.Sci., 15:190-197, 1994.; Carty, T.J. and Marfat, A., "COX-2 Inhibitors, Effectively Alleviate Side Effects of NSAIDs in Inflammatory Diseases", In: EmergingDrugs: Prospect for Improved Medicines. (W.C. Bowman. J.D. Fitzgerald and J.B. Taylor, eds), Ashley Publications Ltd., Chap. 19., pp. 391411). Most commonly used prescription or over-the-counter (OTC) NSAIDs are also often associated with side effects of one kind or another such as stomach ulcers or pain. For example, NSAIDs such as aspirin are known to cause irritation and ulceration of the stomach and duodenum.

WO 94/08922 describes pyridyl ether compounds that enhance cognitive function. US Patent Application Nos. 08/474873 and 08/485537 describe certain substituted pyridyl ether compounds and other compounds that also act on nicotinic acetylcholine receptors to stimulate or inhibit neurotransmitter release. WO 96/31475 describes certain 3-substituted pyridine derivatives which are described as modulators of acetylcholine receptors useful for a number of diseases. While some of these references allude to the potential use of compounds or analogs cited herein for pain management, applicants have discovered that the narrower class of compounds of formula (I) shown below has surprising and unexpected Very effective pain reliever. Applicants have also discovered that activity at nicotinic acetylcholine receptor sites (eg, binding sites) does not necessarily correlate with compound efficacy as analgesics, as some compounds with very high affinity are ineffective as analgesics. Applicants have further discovered that the (R)-enantiomer of this series of compounds is particularly attractive due to its enhanced safety profile relative to the (S)-enantiomer. Applicants have also found that the claimed azetidinyl substituted 3-pyridyl methylene ether compounds are more effective than known non-azetidinyl compounds have stronger activity.

Brief description of the drawings

Figure 1 shows that the compound of Example 4 as the (R)-enantiomer protects rat spinal cord cultures from SP-induced neurotoxicity in a concentration-dependent manner.

Figure 2 shows that when a small dose (0.2umol/kg, i.p.) of the compound of Example 4 was co-administered with varying doses (0-21umol/kg, i.p.) of morphine, effective antinociception was produced in the Mouse Hot Plate Paradigm Effect.

Figure 3 shows the anti-allodynia effect of the compound of Example 4 in the Chung Model of Neuropathic Pain. Light bars reflect responses prior to administration of test compound (Example 4). Dark bars represent the response 15 minutes after administration of the test compound. The compound of Example 4 was compared with saline.

Figure 4 shows the antiallodynic effect during and after repeated administration (i.p.) of 21 umol/kg morphine, compared to the response after repeated administration of saline.

Figure 5 shows that the compound of Example 4 has an obvious anti-nociception effect in the Formalin Model of Persistent Pain (Formalin Model of Persistent Pain) relative to saline (control) and dose increase reduces the nociception response. The doses administered in this trial ranged from 0.1-0.3 umol/kg, p.o. (oral administration).

Figure 6 shows the anti-inflammatory effect of the compound of Example 4 in the carrageenan paw edema model, wherein the compound is as effective as dexamethasone at the indicated doses (panel). Figure 6 also shows that the nicotinic antagonist, mecamylamine, prevents the effect shown by the compound of Example 4 in this model.

SUMMARY OF THE INVENTION

The present invention relates to a method for controlling pain in mammals (including humans), which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal or a human in need of such treatment: Wherein R is selected from H or prodrug derivatives; Z is selected from H, fluorine or chlorine; X is selected from H, fluorine, bromine, chlorine, CN, CHF ₂ , OMe, CH ₂ F or C _1-2 alkyl; And Y is selected from H, fluorine, chlorine, bromine, C _1-6 alkyl, vinyl, ethynyl, 3-propenyl, nitro or OC _1-2 alkyl.

其中R选自H或药物前体衍生物；Z选自H、氟或氯；X选自H、氟、溴、氯、CN、CHF₂、OMe、CH₂F或C_1-2烷基；及Y选自H、氟、氯、溴、C_1-6烷基、乙烯基、乙炔基、3-丙烯基、硝基或OC_1-2烷基。In a preferred embodiment, the administered compound, or a pharmaceutically acceptable salt thereof, has Formula IA:

Wherein R is selected from H or prodrug derivatives; Z is selected from H, fluorine or chlorine; X is selected from H, fluorine, bromine, chlorine, CN, CHF ₂ , OMe, CH ₂ F or C _1-2 alkyl; And Y is selected from H, fluorine, chlorine, bromine, C _1-6 alkyl, vinyl, ethynyl, 3-propenyl, nitro or OC _1-2 alkyl.

The present invention also relates to a method of treating or managing pain in a patient in need of such treatment comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof having the variables described above, wherein said compound is present in the presence of azetidine The 2-position chiral center of the ring is the (S)-enantiomer. In turn, the invention also relates to a method of treating or controlling pain in a patient in need of such treatment, comprising administering to the corresponding (R)-enantiomer, wherein X is selected from fluorine and chlorine; and Y is H, wherein The (R)-enantiomer of the compound of formula (II) has an improved safety profile over the (S)-enantiomer of the same compound.

The present invention also relates to a method of treating pain comprising the co-administration of a compound of formula (I) and an opioid anesthetic such as morphine, wherein the combined administration regimen is more effective in treating pain and has a significant antinociceptive effect. The present invention relates to a method for treating or preventing pain in humans or animals, which comprises administering about 0.2umol/kg (i.p.) of a compound of formula (I) and about 2.6-21umol/kg (i.p.) of morphine to a patient in need of such treatment . The compounds of the present invention may be co-administered with other known safe and effective narcotic analgesics, such drugs are well known to those skilled in the art of analgesia, and such co-administration is included within the scope of the methods herein.

The present invention also relates to novel compounds, which are effective nicotinic acetylcholine receptor modulators and effective pain control agents, wherein said compounds are selected from compounds of formula (IA) or pharmaceutically acceptable salts thereof, wherein Z, The stereochemical structures of Y, X and 2-azetidine are respectively selected from:

H, H, Me(S);

H, H, Me(R);

H, H, CN(S);

H, H, Cl(S);

H, H, Cl(R);

H, H, Br(R);

H, H, F(S);

H, H, F (R);

H, H, CHF ₂ (S);

H, H, OMe(R);

H, Me, Cl(S);

H, Me, Cl(R);

H, Et, F(S);

H, Vinyl, Cl(S);

H, Vinyl, Cl(R);

H, Vinyl, F(S);

H, Vinyl, F(R);

H, ethynyl, Cl(S);

H, ethynyl, Cl(R);

H, Cl, Cl(S);

H, Cl, Cl(R);

H, Cl, F(S);

H, Br, Me(S);

H, Br, Me(R);

H, Br, Cl(S);

H, Br, Cl(R);

H, Br, F(S);

H, Br, F (R);

H, Me, H(R);

H, n-Pr, H(S);

H, Vinyl, H(S);

H, Vinyl, H(R);

H, 3-propenyl, H(S);

H, Cl, H(R);

H, F, H(S);

H, NO ₂ , H(S);

H, OEt, H(S);

Cl, H, H(S);

Cl, H, H(R);

F, H, H(S);

F, H, F(S);

F, H, Me(S); and

F, H, Me(R).

The compounds of the present invention are those compounds which are effective as analgesics, neuronal cell death modulators or anti-inflammatory agents.

The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) having the variables R, X, Y, Z and stereochemical structure, and to dosage forms containing such compositions. The present invention also relates to a process for the production of compounds of formula (I), which process is further described hereinafter, and to key intermediates used in the process.

The compounds of the present invention also relate to derivatives of prodrugs having formula (I), wherein R is selected from the group consisting of alkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, amidomethyl, optionally substituted vinyl and amino formyl. Acyl groups may contain a variety of substituents including optionally derivatized amino acids linked to the nitrogen atom through an amide bond.

Detailed description of the invention

The present invention relates to a method of treating or managing pain comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of formula (I) having the variables Z, X and Y as defined above. The invention also relates to certain compounds and pharmaceutical compositions. For the purposes of the present invention, the terms cited in the claims are defined as follows:

"Patient in need of such treatment" broadly refers to a human or veterinary animal patient in need of a pain reliever or analgesic to alleviate or manage the sensation of pain associated with a temporary (acute) or chronic medical disease or disorder related.

"Pharmaceutically acceptable salts" are defined as those salts which, within the scope of sound medical judgment, are suitable for contact with human and animal tissues without unforeseen toxicity, irritation, allergic reaction, etc., and which are They are intended to be effective as analgesics, neuronal cell death regulators or anti-inflammatory agents. Pharmaceutically acceptable salts are well known in the art. See, eg, S.M. Berge, et al., in J. Pharm. Sci., 66:1-19 (1977). Said salts can be prepared in situ during the final isolation and purification of the compounds of formulas I-III or separately by reaction of the free base function with a suitable organic acid. Representative acid addition salts include p-toluenesulfonate, benzoate, naphthalenesulfonate, hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valeric acid Salt, Oleate, Palmitate, Stearate, Laurosilicate, Borate, Benzoate, Lactate, Phosphate, Tosylate, Methanesulfonate, Naphthalenesulfonate , citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, lauryl sulfate, etc. A preferred salt is p-toluenesulfonate. The inventors have found that p-toluenesulfonate salts are less hygroscopic, more crystalline, and more stable, have higher melting points, and are easier to purify than other salts. Furthermore, p-toluenesulfonate is better suited for pharmaceutical formulations.

"Prodrug" or "pharmaceutically acceptable prodrug" is defined as a compound that is rapidly transformed in vivo (e.g., by hydrolysis in blood and during delivery of the compound itself to the site of pharmacological action) to yield the parent compound . An extensive discussion of the prodrug concept is provided by T. Higuchi and V. Stella in Prodrugs as Novel Delivery Systems, Vol. (14 of the ACS Symposium Series) ACS (1975). Such prodrugs are included within the scope of the methods used herein. Examples of prodrugs include pharmaceutically acceptable non-toxic derivatives of azetidine nitrogen, including amides derived from C ₁ -C ₆ -alkylcarboxylic acids, wherein the alkyl chain is straight or branched, Or amides derived from aromatic acids such as derivatives of benzoic acid. These can be prepared by conventional methods. The amides may also be derivatized from amino acids. Other prodrugs include alkyl derivatives and carbamate derivatives of the azetidine nitrogen. Specific examples of prodrug moieties are exemplified below.

The inventors have found that prodrugs of formula (I) wherein R is other than H are cleaved in vivo to compounds of formula (I) wherein R is H. As an example, N-alkylazetidines have been shown to undergo metabolic dealkylation in vivo. Therefore, analysis of blood samples obtained within 8 hours after IP injection of 1.9 μmol/kg of the N-alkyl compound of Example 98 showed substantial dealkylation to the N-H analog (i.e., Example 98). 8) The process takes place within 15 minutes. The resulting plasma concentrations of the compound of Example 8 were within the range provided by the effective IP dose of the compound, suggesting that the analgesic effect of its N-methyl prodrug is due to its in vivo conversion to the active N-H form. Based on the area under the curve measurement, the conversion was estimated to be 16% for the N-methyl compound. Similarly, IP administration of N-ethyl (Example 99) or N-propyl (Example 100) homologues to rats resulted in in vivo conversion to the compound of Example 8 with improved (54% for N-ethyl, 30% for N-propyl).

Other prodrugs showing analgesic effect are compounds of formula (I) wherein R, Z, Y, X and 2-azetidine stereochemistry are as follows:

Methyl, H, Cl, H, (S),

Methyl, H, H, F, (S),

Methyl, H, Br, Cl, (S),

Methyl, H, H, Cl, (R),

Methyl, H, Br, Cl, (R),

Methyl, H, 3-propynyl, Cl, (S),

Methyl, H, Methyl, Cl, (S),

Methyl, H, F, H, (R),

Boc, H, H, F, (R),

Methyl, H, Ethyl, F, (R),

Ethyl, H, H, Cl, (R),

Methyl, H, H, _CH2F , (S),

Methyl, H, Methyl, Cl, (R),

Ethyl, H, H, Methyl, (S),

Methyl, H, Methyl, Ethyl, (S),

Methyl, H, Cl, F, (S),

Cyclohexylmethyl, H, H, F, (R),

tert-propyl, H, H, Cl, (R),

3-methylbutyn-3-yl, H, H, Cl, (R),

Ethyl, H, H, Methyl, (R),

Methyl, H, Methoxy, H, (S),

tert-butyl, H, H, methyl, (S),

"Pharmaceutically acceptable carrier or diluent" refers to non-toxic, inert solid, semi-solid or liquid fillers, diluents, encapsulating materials and any type of preparation auxiliary materials. Some examples include sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered gum tragacanth; Malt; gelatin, talc; alginate gum; excipients such as cocoa butter and suppository or other waxes; oils such as peanut, cottonseed, safflower, sesame, olive, corn, and soybean oils; glycols such as propylene glycol ; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic Physiological saline; Ringer's solution; ethanol and phosphate buffered solutions, and other nontoxic compatible substances used in pharmaceutical preparations. Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, and flavoring agents, can also be present in the composition, according to the judgment of the pharmacist. Flavors and fragrances, preservatives and antioxidants. Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like. Oil soluble antioxidants and metal chelating agents can also be used.

A "therapeutically effective amount" of an analgesic refers to an amount of the compound sufficient to treat pain to obtain the desired therapeutic response. The term also refers to the inhibition of diseases associated with central and peripheral neuropathic pain, including but not limited to AIDS, cancer, stroke, Parkinson's disease, diabetes, osteoarthritis, tissue damage, surgical intervention, and Amount necessary for neuronal cell death in postherpetic neuralgia) or to ameliorate, reduce or prevent inflammation at the target site. It is understood that the total daily dosage or usage of the compounds and compositions of the present invention is to be determined by the attending physician after sound medical judgment. The specific therapeutically effective dosage level for any particular patient will depend upon a variety of factors, including the severity of the disease and the pain or discomfort being treated; the activity of the particular compound and composition employed, and the age, age, and condition of the patient in need of such treatment. Weight, health status, gender and eating habits. Other factors include the time of administration, the route of administration, the rate of excretion of the particular compound used, the duration of treatment, the drugs used in combination or concurrently with the particular compound used, and the like. The compound of the present invention can be administered to patients or animals in a single dose or in divided doses through various forms or administration routes, and the total daily dose ranges from about 0.001-100 mg/kg (body weight), and preferably 0.01-10 mg/kg/day. Of course, the amount may vary depending on the potency of the particular compound or drug, wherein such ranges may vary down to below 0.001 mg/kg (body weight)/day. Dosage unit compositions may contain such amounts or submultiples thereof to make up the total daily dose.

The term "C ₁ -C ₆ -alkyl" refers to a straight-chain or branched methyl, ethyl, propyl, butyl, pentyl or hexyl group.

The markush structures or variables described above or in the claims are self-explanatory and are standard chemical nomenclature or symbols. The 2-position of the azetidine ring is a chiral center.

The term "improved safety" means that the enantiomers of the invention generally elicit only a lower response to the activation of the nicotinic acetylcholine receptors of the peripheral ganglion, which response, if present, may be incompatible with autonomic (e.g. cardiac Vascular and gastrointestinal) system unwanted side effects. The data in the tables in this specification further support the stated safety properties. Moreover, one (R)-enantiomer was shown to have a 12.8-fold lower affinity for the skeletal muscle subtype of nicotinic acetylcholine receptors, a phenomenon that, if present, may be related to the need for muscle coordination and tone in vivo related to side effects.

The term "potent nicotinic acetylcholine receptor binding agent" means that the compound has a binding affinity (Ki) in at least the micromolar (μM) range in an in vitro screen. Preferred binding affinities are in the nanomolar or picomolar range.

"Nitrogen protecting group "P""is selected from protecting groups generally known to protect nitrogen for chemical modification or manipulation at another molecular site of the molecule. Such groups are defined, for example, in textbooks by Stuart Warren, Organic Synthesis, The Disconnection Approach, pp68-69, (1982) and in various well known organic chemistry texts.

"Leaving group "L""is selected from those well known in the art that are readily displaced by the desired nucleophile to form the compounds of the invention. Of particular use here is p-toluenesulfonate, but any anionic leaving group commonly used for this purpose may also be used. Such groups are defined in the aforementioned reference works by Stuart Warren as well as in standard organic treaties.

As noted above, the present invention comprises a compound of the present invention together with a pharmaceutically acceptable excipient or diluent to form a pharmaceutical composition. Compositions suitable for parenteral injection may contain pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution with sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin, etc.), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable Organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the desired particle size in the case of dispersion, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms is ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and other salts, and the like. Delayed absorption of injectable dosage forms can be produced by the use of substances which delay absorption, for example, aluminum monostearate and gelatin. If necessary, the drugs described herein for the treatment of pain or other diseases or indications may be administered intravenously (IV) for as long as necessary to relieve the patient's discomfort, and should be based on sound medical judgment to determine the best for the individual patient and condition. best dose.

If desired, and for more effective distribution over extended periods of time, the compounds can be incorporated into slow-release or targeted delivery systems, such as polymer matrices, liposomes, and microspheres. They can be sterilized, for example, by passage through a bacteria-retaining filter or by incorporating a sterilizing agent in a sterile solid composition (which can be dissolved in sterile water just before use) or some other sterile injectable medium .

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one commonly used inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, and (a) fillers or bulking agents, such as starch, lactose, , sucrose, glucose, mannitol and silicic acid; (b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) wetting agents such as glycerin; ( d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retarders such as petroleum; (f) absorption enhancers such as quaternary ammonium compounds; (g) humectants such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin and bentonite; and (i) lubricants such as talc, calcium stearate, stearin magnesium sulfate, solid polyethylene glycol, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can also be prepared with coatings and shells, such as enteric coatings and other techniques well known in the art. They may contain a sedative or they may be of composition to release the active compound in a delayed manner in a certain part of the intestinal tract. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compound can also be microencapsulated with one or more excipients as noted above.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, liquid dosage forms for oral administration may also contain inert diluents commonly used in the art, such as water or other solvents suitable for injection, co-solvents and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate , benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, tetrahydrofurfuryl alcohol, Fatty acid esters of polyethylene glycol and sorbitan or mixtures of these substances, etc.

Besides such inert diluents, these liquid dosage forms can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and celery Gum or mixtures of these substances, etc. Compositions for rectal or vaginal administration may also be formulated with known suitable carriers such as cocoa butter or suppository waxes or other substances which are normally solid at room temperature but liquid at body temperature and can thus be released in this manner drug.

Dosage forms for the topical or transdermal administration of a compound of this invention further include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or transdermal patches. If a transdermal patch is used, the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers or propellants, as necessary. Compounds that absorb rapidly through the skin may require formulation incorporating absorption retarders or barrier tablets. Also included are ophthalmic preparations, eye ointments, powders and solutions.

The compounds of the invention may also be delivered in the form of liposomes, which are known to be derived from phospholipids or other esters. Liposomes are formed from mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable liposome-forming ester can be used. Liposomal formulations may also contain other suitable excipients, such as stabilizers, preservatives, excipients and the like. Phospholipids or lecithins are generally preferred. Prescott, ed., Methods in Cell Biology, vol. XIV, Academic Press. New York. N.Y. (1976) describes a method for forming liposomes.

The compounds of the present invention can also be used with peripherally acting anti-cholinergic drugs such as N-methylscopolamine, N-methyl atropine, propensine, methenateline, glycopyrrolate, methiphene, Co-administration of serotonin, mecamylamine or pentamethylpiperidine provided that the added compound does not affect the pain-modulating or other targeting effects of the active ingredient. In addition, the compounds of the present invention may be co-administered with opioid narcotics or analgesics such as morphine, where applicants have shown that when small doses of the compounds of the present invention are administered with opioids such as morphine, And improved pain relief. This "improvement" occurs when a dose of the compound (which is normally less effective in treating pain, such as 2umol/kg, i.p. or less) is combined with increasing amounts of morphine, or may occur at higher doses When the compound of the present invention is used in combination with morphine. In addition, or as an alternative to co-administration with morphine, any known analgesic or anti-inflammatory drug may be co-administered as long as it is not contraindicated or less effective in pain management or relief. Can. Thus, such co-administration includes compounds of the present invention and NSAIDs (including ibuprofen, (S)-ibuprofen, salts of ibuprofen, etc.).

Scheme 1 illustrates the preparation of compounds of the invention wherein P is a nitrogen protecting group such as Boc, Cbz, aryl-substituted Cbz, trifluoroacetyl, phenylsulfonyl, aryl-substituted benzenesulfonyl and known in the art. Other known nitrogen protecting groups (see TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 2nd edition, John Wiley & Sons, New York (1991); X is as defined above; in Scheme 1, R is Y (as defined above), or is a group which can be converted into Y in the following way, wherein, for example, the halogen at the Y position is substituted in one or more steps by C ₁ -C ₆ -alkyl, vinyl, propynyl or ethynyl; ^* denotes chirality Center, according to the raw material, the chiral center can be R or S; and HA is an acid that easily forms a pharmaceutically acceptable salt with an amine, such as toluenesulfonic acid, methanesulfonic acid. Naphthalenesulfonic acid, hydrochloric acid, benzoic acid, lemon acid or tartaric acid.

In Scheme 1, the ether formation reaction can be accomplished by various methods, for example: 1) (a) in the presence of a base such as triethylamine or pyridine, etc., in an inert solvent THF, dimethylformamide or dichloromethane, By treating with tosyl chloride, methanesulfonyl chloride or trifluoromethanesulfonic anhydride, etc., or reacting in pure pyridine, the hydroxyl group of azetidinol 1 is converted into a leaving group; (b) then at about 23 ° C - a temperature of about 120°C (necessary temperature to affect the reaction rate), treatment with a pyridinol of structure 2 under sufficiently basic conditions to cause removal of the phenolic proton of 2, for example using potassium hydroxide or sodium hydroxide in DMF; Alternatively a salt of 2 can be pre-formed, preferably a potassium or cesium salt, by treatment with potassium hydroxide or cesium hydroxide in a suitable solvent such as methanol (which can be evaporated and replaced by a solvent suitable for the coupling reaction described above); (2) by using phosphine such as triphenylphosphine or tributylphosphine and azodicarboxylate derivatives in a suitable solvent such as THF, benzene or toluene, etc. at a temperature of about 0°C to about 40°C, For example, diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, or 1,1-(azobiscarbonyl)dipiperidine can also be used to form ethers (Mitsunobu reaction: see Hughes, Organic Reactions, 42, 335, 1992; Abreo, et al., J. Med. Chem. 1996, 39, 817).

A preferred coupling starts with cooling the Boc-protected alcohol 1 in isopropyl acetate to about 0°C. Add triethylamine. Methanesulfonyl chloride was then added at a rate to maintain the temperature below about 10°C. The solution was then stirred for about 15 minutes, allowed to warm to room temperature and stirred for an additional 4.5 hours. 8% sodium bicarbonate solution was added. The mesylated alcohol was isolated, dissolved in DMF and treated with sodium hydroxide to the appropriate hydroxypyridine. The solution was heated to about 80°C for about 6 hours to form compound 3. Compound 3 was isolated, dissolved in ethanol, and then deprotected with tosic acid at reflux temperature for 2 hours to form the corresponding compound 4 as the mesylate salt.

The precise conditions for N-deprotection depend on the nature of the protecting group P and are described in suitable references, such as Greene and Wuts (op.cit.) or computer databases, such as the Synopsys Protecting Groups Database (Synopsys Scientific Systems, LTD., Leeds, UK) is fully described. For P=Boc, the deprotection is conveniently carried out with a suitable mixture of trifluoroacetic acid and dichloromethane (eg 1:1), or by treatment of compound 3 with hydrochloric acid HCl in an ethereal or alcoholic solvent; for P=Cbz, Then by hydrogenolysis (hydrogen, Pd catalyst, in alcoholic solvents such as methanol or ethanol, or other solvents such as ethyl acetate, wherein the starting material is soluble), or with trimethylsilyl iodide (optionally by well known in the art method, in a halogenated hydrocarbon solvent such as chloroform in situ formation) treatment, for P=trifluoroacetyl, by treating compound 3 with a nucleophile such as metal hydroxide, liquid ammonia; or sodium borohydride; For P = arylsulfonyl, by sodium in liquid ammonia, or with sodium naphthalenide (Sodium naphthalenide) in ether solvents such as dimethoxyethane or with sodium amalgam in alcohol solvents such as methanol, or by electrolytic treatment 3 proceed.

The salt formation step involves: first, isolating the free base 4 by, for example, extraction from an aqueous base into an organic solvent such as diethyl ether, dichloromethane or ethyl acetate; drying the organic solvent with a suitable drying agent, such as sodium sulfate or magnesium sulfate; The solvent is optionally removed and replaced with a suitable solvent such as diethyl ether, ethyl acetate or ethanol; treatment with a solution of acid HA (selected from pharmaceutically acceptable classes, as exemplified above).

In Scheme 2, enantiomerically pure (R)-azetidinol 1 (R=Cbz) was prepared from D-methionine as described by Abreo, et al. (op. cit.). First, treat D-methionine in aqueous sodium hydroxide solution with p-toluenesulfonyl chloride to form N-p-toluenesulfonyl-D-methionine, and then according to Sugano and Miyoshi, Bull.Chem.Soc.Japan, 1973, 46, 669 method, which was treated with MeI followed by 1N NaOH to give α-(N-p-toluenesulfonyl-amino)-γ-butyrolactone. Further conversion to azetidine-2-carboxylic acid was carried out by the method of Miyoshi et al., Chem. Lett. 1973, 5-6. Treatment of the lactone in ethanol with hydrogen bromide gas forms N-p-toluenesulfonyl-g-bromonorvaline ethyl ester. Treatment of the bromoester in DMF with about 4 equivalents of water with sodium hydroxide forms (R)-N-p-toluenesulfonyl-azetidine-2-carboxylic acid (possibly mixed with (S)-p Enantiomers, determined by ¹ H-NMR analysis using amide derivatives of α-methylbenzylamine) (Abreo, et al. op.cit.). Treatment of N-p-toluenesulfonyl-azetidine-2-carboxylic acid with sodium in liquid ammonia affords azetidine-2-carboxylic acid, which is then treated with N-( Benzyloxycarbonyl)oxysuccinimide affords N-Cbz-azetidine-2-carboxylic acid. To remove the contaminating (S)-enantiomer, the N-Cbz derivative in methanol was treated with D-tyrosine hydrazide to form an insoluble salt of the (R)-enantiomer, which was collected by filtration. The optical activity of the subsequently released free acid is [α] _D =+105.4 (c4.0, _CHCI3 ). Treatment of the free acid with borane·THF affords 1 (R=Cbz). The S-enantiomer ((S)-1) can be synthesized similarly starting from L-methionine. If enantiomer enrichment is desired, the product can be optically resolved using D-tyrosine-hydrazide in a similar manner to that described above. Other protecting groups, such as Boc, are readily added by standard methods, for example, by reacting the intermediate or Cbz deprotected azetidine-2-carboxylic acid with appropriate standard reagents under the conditions described (Greene and Wuts, see above).

a.Abreo，等，J.Med.Chem.1996，39，817.Process 2

a. Abreo, et al., J. Med. Chem. 1996, 39, 817.

Alternatively, according to Scheme 3, racemic azetidine-(2)-carboxylic acid can be prepared from γ-butyrolactone according to the method of Rodebaugh and Cromwell, J. Het. Chem., 1969, 6, 435 5. Treatment of gamma-butyrolactone with bromine and catalytic phosphorus or phosphorus tribromide followed by benzyl alcohol and hydrogen chloride gas yields benzyl alpha, gamma-dibromobutyrate. Treatment of the dibromide with 1 equivalent of benzhydrylamine in a suitable solvent such as ethanol or acetonitrile affords benzyl N-benzhydrylazetidine-2-carboxylate. Hydrogenolysis over a palladium catalyst such as palladium hydroxide affords racemate 5. According to the method of Rodebaugh and Cromwell, J.Het.Chem., 1969, 6, 993, the corresponding N-Cbz derivatives were resolved to provide (R)- or (S)-N-Cbz-nitroheterocycles, respectively Butane-2-carboxylic acid 6. Thus, treatment of a solution of compound 5 in aqueous base with benzyl chloroformate affords racemic N-Cbz-azetidine-2-carboxylic acid. Treatment of the methanolic solution of the racemate with L-tyrosine hydrazide resulted in the precipitation of the R-enantiomer as an insoluble salt, which was further worked up as described in the accompanying text to Scheme 2. The pure (S)-enantiomer was obtained from the soluble fraction according to the method of Rodebaugh and Cromwell, J. Het. Chem., 1969, 6, 993 .

Process 3 a. Rodebaugh and Cromwell, J. Het. Chem.1969, 6, 435 b. Rodebaugh and Cromwell J. Het. Chem. 1969, 6, 993. c. Abreo, et al., J. Med. Chem.

In addition, according to Scheme 4, (R)-1 was prepared by a new method using (R)-azetidinone 7 as starting material, and the starting material was obtained from D- Preparation of diesters of aspartic acid. Triethylamine hydrochloride formed during the disilylation process is preferably consumed with an excess of RMgX. Thus, treatment of the ethereal solution of the free base of D-aspartate dibenzyl ester with trimethylsilyl chloride and triethylamine gave the intermediate N-silyl derivative, which was treated with tert-butylmagnesium chloride to give 7. Alternatively, the trimethylsilyl group in this method can be replaced by a silyl group such as tert-butyldimethylsilyl (as demonstrated by Baldwin et al.), which can be removed with fluoride ion. At -20°C-40°C, in an ether solvent, with a suitable reducing agent such as diisobutylaluminum hydride (DIBAL), lithium aluminum hydride, aluminum hydride, mono- or dihaloaluminum hydride, or aluminum trichloride Treatment of 7 in a mixture with lithium aluminum hydride reduced the 2-carbonylbenzyloxy group to the hydroxymethyl group and the azetidinone carbonyl group to the methylene group. The scope of this novel transformation method is intended to include other esters, such as C1-C6 alkyl esters, and, where appropriate, the stepwise reduction of the ester group and the azetidinone carbonyl. The benzyl ester is preferably hydrogenolyzed to the free acid prior to reduction of the carbonyl moiety. For example, according to the method of Salzmann, et al., (J.Am.Chem.Soc.1980, 102, 6163-6165), treat 7 with sodium borohydride in methanol at room temperature, or preferably at low temperature (-20°C- 10 °C) in ether or ether alcohol mixtures, treatment of 7 with lithium borohydride or calcium borohydride provided selective reduction of the ester group to give the corresponding azetidin-2-one-4-methanol ( Tanner and Somfai (Tetrahedron Lett. 1987, 28, 1211-1214) found an additional multistep process to this intermediate in the (S)-enantiomer series). Subsequent reduction of the azetidinone carbonyl group with a suitable reducing agent such as lithium aluminum hydride, aluminum hydride, mono- or dihaloaluminum hydride, or a mixture of aluminum trichloride and lithium aluminum hydride as described above provides the intermediate azetidinone Cyclobutane-2-methanol. Other methods of reducing the azetidinone carbonyl can be envisioned, for example, with phosphorus pentasulfide or Lawesson's reagent, followed by conversion of the azetidinone carbonyl to the thioamide by reduction, for example in the presence of nickel. N-protection of the intermediate azetidine-2-methanol can be carried out using standard conditions, eg, treatment of the intermediate secondary amine with di-tert-butyl dicarbonate, to provide the product (R)-1 (P=Boc). The process from 7 to (R)-1 (R=Boc) is illustrated by a one-step reduction with lithium aluminum hydride in ether at 0°C to room temperature, and the intermediate secondary amine is isolated by standard separation techniques (cf. Fieser and Fieser, Reagents for Organic Synthesis.vol.1.p.584), followed by N-protection with Boc to maintain high chiral purity (>98%ee). Similar to the preparation of (R)-1 starting from D-aspartic acid, (S)-1 can be prepared from L-aspartic acid.

Process 4

a.Baldwin, etc., Tetrahedron 1990,46,473348 prepare various 5-and/or 6-substituted pyridin-3-alcohol 2 methods as follows: pyridin-3-alcohol (2, X=R=H) can be obtained from Commercially available (eg Aldrich).

6-Methylpyridin-3-ol (2, X=Me, R=H) is commercially available (eg Aldrich).

5-Chloropyridin-3-ol (2, X=H, R=C) is commercially available.

5,6-dichloropyridin-3-ol (2, X=R=Cl) and 5-bromo-6-chloropyridin-3-ol (2, X=Cl, R=Br) can be obtained according to Koch and Schnatterer (Synthesis, 1990, 499-501) from commercially available 2-hydroxy-5-nitropyridine (eg Aldrich). Thus, separate treatment of 2-hydroxy-5-nitropyridines with potassium chlorate or bromine each affords 2-hydroxy-3-halo-5-nitropyridines, which are treated with phosphorus oxychloride in the presence of quinoline to provide the respective 2 -Chloro-3-halo-5-nitropyridine. Under acidic conditions, treatment with iron or tin can reduce the nitro group to give the respective 5-amino-2-chloro-3-halopyridines. Diazonium intermediate with sodium nitrite in the presence of fluoboric acid or with alkyl nitrite in the presence of boron trifluoride gives the intermediate diazonium salt which is heated with acetic anhydride to give 5-acetoxy-2-chloro Substituted-3-halo-pyridine 8. A key step in the whole process is the conversion of 3-amino to 3-hydroxy under the conditions shown in Scheme 5.

Process 5

Scheme 5 describes the diazotization of 8 with alkyl nitrite in the presence of boron trifluoride etherate to give the intermediate diazonium salt, which is heated with acetic anhydride to give 5-acetoxy-2-chloro- 3-Halo-pyridines 9. Alternatively, the diazotized intermediate can be prepared using sodium nitrite under acidic conditions as described by Koch and Schnatterer (Synthesis, 1990, 499-501). Under mild basic conditions, hydrolysis or alcoholysis of the acetoxy group of 9 affords 2 (X=Cl, R=Br or Cl).

According to the method of Effenberger et al. (Chem. Ber., 1992, 125, 1131-1140), by treatment with sodium nitrite in the presence of aqueous sulfuric acid, followed by heating with aqueous sulfuric acid and extraction, or preferably according to scheme 5 (where R=H) the conditions shown, through the improved approach, can prepare 6-chloropyridin-3-alcohol (2, X=Cl, R=H) from commercially available 2-chloro-5-aminopyridine .

According to conditions similar to Scheme 5, 5-methyl-6 can be prepared from commercially available (Maybridge) 2-chloro-3-methyl-5-nitropyridine by reduction of the nitro group (Fe, HOAc). -Chloropyridin-3-ol.

Process 6 a. Clark and Macquarrie, Tet. Lett. 1987, 28, 111-114

According to Scheme 6 (see above), under conditions similar to Scheme 5, 6-fluoropyridin-3-ol (2, X=F, R=H) and 6-fluoro-5-methylpyridin-3 -Alcohols (2, X=F, R=Me) can be prepared from the corresponding 3-amino compounds 11 . Compound 11 was prepared by catalytic reduction of the corresponding 3-nitropyridine derivative derived from commercially available 6-chloro Material 10 was prepared. Thus, for example, heating a solution of 10 in acetonitrile with potassium fluoride in the presence of tetraphenylammonium bromide affords 11.

Process 7

Intermediate 2 (from Scheme 1) was prepared according to Scheme 7 (X=H, R=F or Br). Treatment of commercially available 3,5-dibromopyridine with an anion of benzyl alcohol, such as sodium benzide in DMF, at room temperature affords the monobenzyloxy compound 12. Debenzylation of 12 by heating in 48% hydrogen bromide in acetic acid gave 2 (X=H, Y=Br). Treatment of a methanolic solution of 12 with liquid ammonia followed by heating in a steel kettle at 120°C-150°C for 16-48 hours in the presence of a copper salt such as copper(I) bromide affords compound 13. Treatment of 13 with an alkyl nitrite such as tert-butyl nitrite in the presence of boron trifluoride etherate in an inert solvent such as dichloromethane affords the intermediate diazonium tetrafluoroborate, which is dissolved in acetic anhydride , or preferably heated at 50°C-90°C in an inert solvent such as toluene to give 3-benzyloxy-5-fluoropyridine. Stirring the benzyloxy compound at room temperature in the presence of a palladium(0) catalyst such as 10% palladium on carbon under hydrogen in a suitable solvent such as methanol, ethanol or ethyl acetate affords 2 (X=H, R=F) .

Process 8

Intermediate 2 (X=F, R=Br) was prepared according to Scheme 8. Treatment of compound 2 (X = F, R = Br) (prepared as described in Scheme 7) with an aryl diazonium salt, such as commercially available p-nitrophenyltetrahydroborate diazonium salt, affords the diazo coupling Product 14. Reduction of the diazo group by treatment with, for example, tin chloride in ethanol and hydrochloric acid provides the intermediate 2-amino-3-bromo-5-hydroxypyridine, which is diazotized with simultaneous or subsequent treatment with fluoride ion , to obtain the fluorinated compound 2 (X=F, R=Br). For example, treatment of intermediate 2-amino-3-bromo-5-hydroxypyridine with sodium nitrite at 0°C-70°C in the presence of HF·pyridine affords 2 (X=F, R=Br).

Process 9

a. Odashima et al., Bull Chem Soc Jpn 1993, 66, 797-803

According to Scheme 9, from 3-bromo-2-chloro-5-nitropyridine (V. Koch and S. Schnatterer Synthesis, 1990, 499-501) prepared intermediate 2 (X=Me, R=Br). Treatment of the starting material with the sodium salt of diethyl malonate followed by hydrolysis and decarboxylation replaces the 2-chloro group with a methyl group. An intimate mixture of 3-bromo-2-chloro-5-nitropyridine and sodium diethylmalonate was heated at 100°C for about 1 hour. , followed by heating the resulting mixture at reflux in the presence of 12N sulfuric acid for about 16 hours to give the methylated product. For example, under acidic conditions, such as in the presence of aqueous acetic acid, reduction of the nitro group with iron or tin gives amino compound 15, which can be converted to 2 (X=Me, R=Br) under conditions similar to Scheme 5.

Process 10

Other compounds of the present invention are prepared according to scheme 10, wherein starting material 3 is prepared as described in scheme 1, and the suitable pyridyl alcohol 2 used is again as scheme 5 (for 2, X=Cl, R=Br), or scheme 7 (for 2 , X=H, R=Br), process 8 (for 2, X=F, R=Br), or process 9 (for 2, X=Me, R=Br). The bromo substituent is then replaced via a transition metal-catalyzed cross-coupling reaction, which can occur under various conditions depending on the nature of Z. Bromo compound 3 (R=Br, preferably X=H or Me) in THF was treated with 1-3 equivalents of methylmagnesium bromide in the presence of (dppp) _NiCl2 at 40°C-70°C in diethyl ether 16 was obtained (Z=Me); when X=Cl or F, this method was less satisfactory than the alternative method disclosed in this specification. The brominated compound 3 (R=Br ) to give compound 16 (Z = vinyl or allyl). Treatment with an excess of trimethylsilylacetylene or propyne and catalyst tetrakis(triphenylphosphine)palladium optionally in a sealed tube under heating at 80°C-110°C in the presence of a copper salt such as copper(I) iodide Bromination of compound 3 (R = Br) in toluene or benzene affords compound 16 (Z = trimethylsilylethynyl or propyn-1-yl). In the presence of a catalytic amount of a palladium(II) salt such as palladium(II) acetate, a triarylphosphine such as tri-o-tolylphosphine, and a base such as triethylamine, optionally in a sealed container at 60°C to 120°C Treatment of brominated compound 3 (R = Br) in a nitrile solvent such as acetonitrile or propionitrile with excess C ₄ -C ₆ alk-1-ene with heating affords compound 16 (Z = C ₄ -C ₆ alkenyl) . Compound 17 (where Y = ethynyl) can be prepared by treating the corresponding compound 16 (Z = trimethylsilylethynyl) with excess potassium carbonate in methanol at room temperature - 400C for 1 - 24 hours. In the presence of a platinum catalyst such as 5% platinum on carbon, under hydrogen, in a solvent such as methanol, ethanol or ethyl acetate, by stirring the corresponding compound 16 (Z = vinyl, allyl, propynyl or C ₄ - C ₆ alkenyl) can prepare compound 17 (wherein Y=C ₂ -C ₆ alkyl). Compound 17 or compound 16 (Z=Y) is converted to a compound of the invention by deprotection and salt formation using methods selected from those described in Scheme 1, e.g., by treatment with 1:1 trifluoroacetic acid/dichloromethane. N-Deprotection of 16 or 17 (P=Boc).

As noted above, the compounds of the present invention can be prepared by a process comprising (I) combining an azetidine of formula 1 (wherein P is as defined above) with a polysubstituted pyridyl compound of formula 2 (wherein R and X are as above defined) contact, coupling and deprotection, wherein Y is selected from C ₁ -C ₆ alkyl, vinyl or ethynyl compound of formula I or the precursor of compound of formula I.

The term "contacting" means bringing a modified variant of Formula 1 or 1 selected from a compound of Formula 1' with a polysubstituted pyridine under conditions necessary to effect the coupling of 1 or 2 to yield (deprotected) the desired product Compound 2 or its derivative contact, and described formula I ' compound structure is as follows: wherein L is a leaving group represented by tosylate, mesylate or triflate, which can be obtained by making compound 1 in the presence of a base such as triethylamine or pyridine or in pure pyridine It is prepared by reacting with toluenesulfonyl chloride, methanesulfonyl chloride or trifluoromethanesulfonic anhydride in an inert solvent such as THF, dimethylformamide or dichloromethane, and the product is obtained after deprotection. The preferred reaction condition is usually in solution.

"Derivatives thereof" as specifically referred to above are selected from compounds of formula 2 in which the phenolic proton is blotted (removed) leaving a nucleophilic anion or from potassium or cesium salts of deprotonated derivatives of formula 2. Its derivatives are also selected from Mitsunobu intermediates. Compounds 1 and 2 are reacted with phosphines such as triphenylphosphine or tributylphosphine and diphenylphosphine in a suitable solvent such as THF, benzene or toluene at a temperature of about 0 to about 40°C. Azodicarboxylates such as ethyl azodicarboxylate, di-tert-butyl azodicarboxylate or 1,1'-(azodicarbonyl)dipiperidine are contacted to form the intermediate.

More particularly, the present invention relates to a process for the production of the R-enantiomer comprising:

(a) preparing a compound of formula 1 or its 1' derivative having a (R) stereochemical structure at the azetidine 2-position;

(b) preparation of formula 2 compound or its derivative 2';

(c) contacting the reactant formed in step (a) with the reactant formed in step (b) under suitable conditions to form a compound of formula 3;

(d) Deprotecting the compound of formula 3 under suitable conditions to form the R-enantiomer.

Alternatively, steps (a')-(b') can be carried out using the (S)-enantiomer of step (a) above to form the formula at the 2-position of the azetidine as the (S)-enantiomer I compound.

The present invention also relates to a process as described above, further comprising a step (e) (or (e') in the case of the (S)-enantiomer) comprising adding the acid HA to step (d) ( or (d')) to form a compound of formula 4 (or its (S)-enantiomer in case of (e')).

biology program

Compounds of the invention were subjected to the in vitro assay described below against the nicotinic acetylcholine receptor and were found to be potent binders of this receptor. In vitro functional assays were also performed to evaluate the ability of the compounds to modulate the function and neuroprotection of the nicotinic acetylcholine receptors associated with ion flux. In addition, the compounds of the present invention were evaluated using known animal models of pain or nociception and anti-inflammatory effects, which are used to predict pain properties in higher mammals, including humans (Sheen, K. and Chung, J.M., Brain Res., 610: 62-68, 1993). The association of animal neuropathy models with chronic pain in humans has been described by Seltzer (Neurosciences, 7:211-220, 1995).

The compounds of the present invention have been found to be useful as nicotinic acetylcholine receptor binding agents and as potent analgesics. The experiments described below demonstrate that the compounds of the present invention are effective in animal pain models. In addition to the general analgesic properties of the compound, the (R)-enantiomer generally has an improved safety margin relative to the (S)-enantiomer of the same Peripheral side effects associated with activation of ganglion-like receptors and peripheral side effects associated with activation of skeletal muscle-like nicotinic acetylcholine receptors) were demonstrated. Data demonstrating this improved margin of safety are also presented below.

In vitro protocol

Protocol for Determination of Binding Potency of Ligands to Nicotinic Acetylcholine Channel Receptors

[ ³ H]-Cydidine ([ ³ H]-CYT) binding to neuronal nicotinic acetylcholine receptors was assayed using crude synaptic membrane preparations from rat whole brains (Pabreza et al., Molecular Pharmacol., 1990, 39:9). The washed membranes were stored at -80°C until use. Frozen aliquots were slowly thawed and suspended in 20 volumes of buffer (containing: 120 mM NaCl, 5 mM KCl, 2 mM Magnesium Chloride. 2 mM Calcium Chloride and 50 mM Tris-Cl, pH 7.4 at 4°C). After centrifugation at 20000 xg for 15 minutes, the pellet was resuspended in 30 volumes of buffer. Homogenates (containing 125-150 μg protein) were added in triplicate to tubes containing test compounds and [ ³ H]-CYT (1.25 nM) in a final volume of 500 μl. Samples were incubated at 4°C for 60 minutes and then rapidly filtered through Whatman GF/B filters (pre-soaked in 0.5% polyethyleneimine) using 3 x 4 ml of ice-cold buffer. The filtrate was counted in 4 ml Ecolume(R) (ICN). In the presence of 10 [mu]M (-)-nicotine, non-specific binding was determined and values expressed as a percentage of total binding. The IC ₅₀ value was determined by RS-1(BBN) nonlinear least squares curve-fitting equation, and the IC ₅₀ value was converted into Ki value by Cheng and Prusoff correction (Ki=IC ₅₀ /(1+[ligand]/ligand Body Kd)). Alternatively, data can be expressed as a percentage of total specific binding. The binding data (see Table 1) suggest that the compounds of the invention have high affinity for neuronal nicotinic acetylcholine receptors.

Table 1 Ex. * x Y [ ³ H]CYTKi(nM) 6 R h h 0.04 4 R Cl h 0.05 8 R f h 0.06 11 R h f 0.34 14 R h Me 0.18 16 R Cl Cl 0.06 18 R Cl Br 0.02 97 ^* R h h 85 114 R h h 0.12 115 R Me h 0.07 118 ^** R Me h 4.8 119 R OMe h 0.67 124 R Me Br 0.03 125 R f Br 0.04 127 R Cl Me 0.06 128 R Br h 0.17 129 R f vinyl 0.09 7 S h h 0.04 19 S Cl h 0.04 9 S f h 0.16 20 S Me h 0.06 10 S h f 0.09 twenty one S h Cl 0.04 12 S h Br 0.26 13 S h Me 0.05 twenty three S h Et 0.11 twenty four S h n-Pr 0.05 twenty two S h vinyl 0.97 15 S Cl Cl 0.02 17 S Cl Br 0.02 25 S Cl Me 0.05 27 S Cl Et 0.04 28 S Cl n-Pr 0.03 29 S Cl n-Bu 0.16 26 S Cl vinyl 0.24 30 S Cl Ethynyl 0.04 31 S f Br 0.03 32 S f Me 0.10 33 S f Cl 0.04 34 S Me Br 0.02 36 S Me Et 0.04 35 S Me vinyl 0.22 113 S CHF2 h 0.17 116 ^** S f h 0.34 117 ^** S Me h 0.17 120 S h OEt 0.04 121 ^* S h h 2.3 122 ^** S h h 0.10 123 S CN h 1.9 126 S f Et 0.07 130 S h 3-propenyl 0.04 131 S f vinyl 0.13 132 S h NO2 0.33

^* Compound also has 2-chloro substituent

^** Compounds also have 2-fluoro substituents

Tissue Isolation from a Torpedo California Electroplate Model to Characterize Nicotinic Acetylcholine Receptors in Mammalian Neuromuscular Junction Receptors. To this end, compound binding was determined using a solid phase binding assay measuring the binding of [ ¹²⁵ I]α-bungarotoxin (106 Ci/mmol) to tissue isolates. At 4°C, each plate of a 96-well microtiter plate (Immulon Removawells Strips, Dynatech, Chantilly, VA) was coated with 0.5 μg Torpedo membrane (ABS Inc., Wilmington, DE) in 50 mM sodium bicarbonate buffer (pH 9.6). Hole for 12 hours. The wells were then washed twice with phosphate buffered saline (PBS) and quenched with 5% bovine serum albumin (BSA) for 1 hour. Then [ ¹²⁵ I]α-bungarotoxin (approximately 1.9 nM/100 μl 10 mM phosphate buffer, pH 7.4/0.2% BSA) was added (acted) to each well for one hour. For competition assays, increasing concentrations of competitor (50 μl) were added to wells in triplicate, followed by 50 μl of [ ¹²⁵ I]α-bungarotoxin and incubated for 1 hour. Non-specific binding was determined in the presence of 1 [mu]M [alpha]-bungarotoxin. After incubation, the wells were washed 5 times with PBS. The contents of each well were placed into individual vials and radioactivity was measured with a gamma counter (Model 5000, Beckman, Fullerton, CA).

The data in Table 2 demonstrate that the (R)-enantiomer of the compound of Example 4 has a 12.8-fold lower affinity (i.e., increased selectivity) for the neuromuscular junction nicotinic acetylcholine receptor than it does for the [ ³ H]-field The comparable activity of ancholine-labeled neuronal nicotinic acetylcholine receptors constitutes a comparison (Table 1). These data indicate that the compound of Example 4 is safer and causes fewer motor (systemic) or respiratory (systemic) complications than its (S)-enantiomer.

Table 2 Ex. * x Y Ki(nM)α-Bungarotoxin 19 S Cl h 1300 4 R Cl h 16,600

Protocol for Assaying the Ability of Nicotinic Acetylcholine Receptor Ligands to Activate Receptors in Peripheral Ganglia

The human neuroblastoma clonal cell line IMR-32 cells (ATCC, Rockville, MD) were maintained in logarithmic phase of growth according to established methods. Test cells were seeded in 24-well tissue culture plates at a density of 500,000 cells/ml. Cells in the culture plate were allowed to proliferate for 48 hours before adding 2 μCi/ml of ⁸⁶ Rb ⁺ (35 Ci/mmol) overnight at 37°C. ⁸⁶ Rb ⁺ flux assays have been performed according to a previously published protocol (Lukas, RJ, J. Pharmacol. Exp/Ther., 265:294-302, 1993), but after ⁸⁶ Rb ⁺ addition, washout and agonist-induction Serum-free Dulbecco's modified medium was used in the flow-through step. Data reflect the activity of the ⁸⁶ Rb ⁺ flux at a concentration of 1 μM and reflect this response as a percentage of the maximal response elicited by (S)-nicotine. The data also indicate that the greater the response, the more effective the activation of peripheral ganglion receptors, which further suggests that stronger undesired effects would occur in vivo, for example, in the cardiovascular and/or gastrointestinal system.

Table 3 compares the activation data of ⁸⁶ Rb ⁺ flow in the IMR-32 cell line of the paired enantiomers of the compounds of the present invention. The data indicated that in most cases (5 out of 6 listed), the (R)-enantiomers in each pair were less potent than the corresponding (S)-enantiomers in activating ^{Rb +} flux . Thus, the (R)-enantiomer is expected to reduce side effects eliciting peripheral autonomic nicotinic acetylcholine receptors (eg in the cardiovascular or gastrointestinal system).

table 3 Examples# * x Y % maximal response of IMR-32 to nicotine at 1 μM compound concentration 4 R Cl h 97 19 S Cl h 173 8 R f h 46 9 S f h 103 16 R Cl Cl 85 15 S Cl Cl 117 18 R Cl Br 93 17 S Cl Br 120 11 R h f 31 10 S h f 28 14 R h Me 15 13 S h Me 27

Protocol for the determination of the efficacy of nicotinic acetylcholine receptor ligands as agents to prevent cell death in spinal cord neurons

(-)-nicotine, ABT-418, ABT-089 and related nicotinic acetylcholine receptor ligands have indicative neuroprotective properties in vivo and in vitro (Akaike, A., et al., Brain Res., 644:181 -187, 1994; Donnelly-Roberts et al., Brain Res., 729:36-44, 1996; Marin, P., et al., Neuroreport, 5:1977-1980, 1994; Martin, E.J., et al., DrugDev.Res., 31:135-141, 1994; Shimohama, S., et al., Annals New York Academy of Sciences, 356-361, 1996).

The efficacy of the compound of Example 4 against neurotoxicity in a model associated with neuropathic pain and spinal nerve degeneration is detailed below.

Primary spinal cord cultures of mixed size and diameter motor neurons were prepared from 13 day gestation Sprague-Dawley rats as described by Regan and Choi (J. Neuroscience, 43:585-591, 1991). The cells were plated on poly-L-lysine-coated 96-well culture plates at a density of about 50,000 cells/well with L15 medium containing 2% horse serum (HS)/33mM glucose/ 2mM glutamine/50U/ml blue:streptomycin/B27 complement/10mg/ml (nerve growth factor) NGF. To exclude fibroblasts and Schwann cells from spinal cord cultures, antimitotic medium (L15 without horse serum plus 10 mM uridine (uridine) and 10 M M 5-fluoro-2'exoxy- uridine) for 2 days. Cultures were maintained at 36°C/10% carbon dioxide.

After 7 days in vitro (DIV), cells were pretreated for 2 hours with test compounds diluted in L-15 medium containing B27 complement. The pre-treatment solution was replaced by HBSS (no magnesium but with 3 mM calcium chloride) containing substance P (SP) (30 μM) or 300 μM glutamine (Glu) and co-administered with the test compound for an additional 15 minutes. The compound/treated solution was removed and replaced with fresh L-15/B27 medium for 24 hours. Assessment of neuronal damage was performed by 1) measuring the level of the cytosolic enzyme lactate dehydrogenase (LDH) released by injured cells into the medium or 2) staining with 4% Trypan blue for 5 minutes , to evaluate morphological damage by light microscopy. LDH release was quantified using the Cytotox 96 assay kit (Promega; Madison, WI) as described above (Donnelly-Roberts, op. cit.). Basal LDH release was generally between 6-9% of LDH release following lysis of cells with 0.8% Triton X-100, whereas impairment generally caused a 2-3 fold increase over basal levels. To enable plate-to-plate comparisons, all values were normalized to 30 μM SP-induced maximal LDH release (designated as 100%). These toxic events are receptor-mediated, because the effect of SP can be blocked by the SP receptor antagonist, spantide II (100 μ M), and the toxicity induced by Glu-induced by the NMDA receptor antagonist, MK-801 ( 1 μM). However, these induced toxicities may be mechanistically different since MK-801 does not prevent SP-induced toxicity.

These results demonstrate that the compound of Example 4 is more effective than NMDA receptor antagonists in inhibiting a broad spectrum of toxic events. Compared with MK-801, the compound of Example 4 reduced SP and Glu-induced neurotoxicity, and its neuroprotective EC ₅₀ was 10 μM ( FIG. 1 ). However, the (S)-enantiomer, the compound of Example 19, was 10-fold less potent as a neuroprotectant in the spinal cord (EC ₅₀ =100 mM). This neuroprotective effect can be blocked by selective nicotinic antagonists, mecamylamine (10 μM), methyl bovine pentine (MLA, 10 nM) and α-bungarotoxin (α-BTX, 1 nM), indicating that neuroprotection Mechanism of nicotinic receptors. These results suggest that the compound of formula (I) is effective in the treatment or prevention of mammals, including the method of human neuronal cell death, and therefore can be used for the treatment of disorders related to central and peripheral neuropathic pain-related diseases, including AIDS , cancer, stroke, Parkinson's disease, diabetes, osteoarthritis, tissue damage, surgical intervention, and post-treatment neuralgia. Accordingly, the present invention also includes a method of treating neurotoxicity or degeneration of the spinal cord comprising administering a therapeutically effective amount of a compound of formula I to a patient in need of such treatment. A preferred compound is the R-enantiomer.

In vivo protocol

Protocol for Determining the Potency of Nicotinic Acetylcholine Receptor Ligands as Analgesics in the Mouse Hot Plate Paradigm

A separate group of mice (n=8/group) was used for each dose group. All drugs were administered by intraperitoneal route. The hot plate test was performed 30 minutes after dosing the animals. The heating plate used was an automated heating plate pain monitor (model# AHP16AN, Omnitech Electronics, Inc., Columbus, OH). The hot plate temperature was maintained at 55°C and a cutoff time of 180 seconds was used. The latency up to the 10th jump is recorded as a secondary measurement. The increase in latency to the 10th jump relative to the control group is believed to be an antinociceptive effect. Table 4 shows, among the doses tested, the minimum effective dose (MED) at which a significant antinociceptive effect as defined above of the compounds of the invention was observed. The data show that the compounds of the present invention generally exhibit significant antinociceptive effects in the dose range of 0.062-62 μmol/kg (ip injection).

Protocol for Determining the Potency of Nicotinic Acetylcholine Receptor Ligands as Analgesics for Neuropathic Pain in the Chung Model

The Chung neuropathic pain model was generated by unilateral ligation of the L5 and L6 nerves (nerves innervating the hindlimb) in rats (male, Sprague-Dawley) (Kim and Chung, Pain, 1992, 50, 355-63). After a sufficient recovery period, these animals exhibited allodynia (withdrawal response to normal non-painful stimuli) in response to tactile stimuli (i.e., VonFrey hairs). The response was quantified by determining the 50% threshold of the response to different weights of Von Frey hairs. These hairs were applied to the mid-toe region of the hindpaw ipsilateral to the ligation site. The animals were tested repeatedly over a period of 120 minutes. A crossover design was used for each animal tested following daily administration of saline and each dose of test compound. An antiallodynic effect is considered to be present when the 50% threshold of the group treated with the test compound is significantly increased compared to the 50% threshold of the group treated with normal saline.

The antiallodynic effect is considered to exhibit strong efficacy in the treatment of neuropathic pain. Selected compounds of the invention were tested in this model of neuropathic pain and the results are shown in Table 4. The table shows the minimum effective dose (MED) at each dose tested at which selected compounds produced a significant increase in the threshold of 50% compared to the control group. These data indicate that 7 of 8 test compounds showed significant effects at at least one of the doses tested, and that significant effects were observed in the dose range of 0.19-0.62 μmol/kg (ip).

Table 4 Ex. * x Y MED heating plate model (μmol/kg.ip) MEDChung model (μmol/kg.ip) 6 R h h NS 4 R Cl h 0.62 0.3 8 R f h 1.9 0.62 11 R h f NS 14 R h Me 62 16 R Cl Cl 6.2 0.19 18 R Cl Br 0.62 7 S h h 6.2 19 S Cl h 0.62 0.3 9 S f h 0.62 20 S Me h 0.62 10 S h f 6.2 0.62 twenty one S h Cl NS 12 S h Br NS 13 S h Me NS twenty three S h Et NS twenty four S h n-Pr 62 15 S Cl Cl 1.9 NS 17 S Cl Br 1.9 0.19 25 S Cl Me 0.062 27 S Cl Et NS 28 S Cl n-Pr NS 29 S Cl n-Bu NS 26 S Cl vinyl 1.9 30 S Cl Ethynyl 6.2 31 S f Br 6.2 32 S f Me HS 34 S Me Br 0.62 36 S Me Et NS 35 S Me vinyl NS 122 ^** S h h - 1.9 NS = No significant effect was observed at the dose tested compared to the normal saline control group. ^** Compounds also have a 2-fluoro substituent.

As shown in Table 4, the (S) or (R) series of some compounds showed no activity in the analgesic model. Methods of treating or preventing pain comprising administering a compound of formula (I) wherein X and Y are as previously defined exclude those specific (S) or (R) compounds as indicated above which are inactive in pain models. Compounds that exhibit activity or are likely to exhibit activity in later modified pain models are included within the scope of the claimed methods. Compounds of formula (I) also have activity as neuronal cell death and/or inflammation ameliorating agents.

Protocol for Determining the Potency of Nicotinic Acetylcholine Receptor Ligands to Interfere with Exercise Performance in Rotarod Appartus

Motor coordination was assessed with an accelerating rotarod apparatus (Omnitech Electronics, Inc. Columbus, OH). Motor capacity was monitored in a 41 x 41 cm open plane with a photobeam activity system (San Diego Instruments, San Diego, CA) in dim light. Mice were placed on a 3.5 cm diameter round rod whose rotational speed was increased from 0 to 40 rpm over 120 seconds. The time it takes for the mouse to fall from the rod is recorded with a maximum range of 120 s. Twenty-five minutes after receiving (ip injection), mice were placed on an open surface for 5 minutes. The rotarod test was performed immediately after the mice were removed from the open plane (ie 30 min after injection). About 35 minutes after the injection, a thermometer was inserted 3 cm into the rectum to measure body temperature. (YSI Tele-Thermometer, Yellow Springs Instrument Co., Inc., Yellow Springs, OH). Diazepam (10.5 μmol/kg, i.p.) was used as a positive control.

The compound of Example 8 was tested in the exercise capacity, body temperature and rotarod test and showed no effect in the rotarod test until dose 19 was reached. In comparison, the compound of Example 9 (0.62 μmol/kg) showed impairment in 2 out of 3 experiments. This demonstrates that the (R)-enantiomer (Example 8) has fewer motor coordination side effects than the (S)-enantiomer (Example 9).

Protocol for Determination of the Potency of Nicotinic Acetylcholine Receptor Ligands as Analgesics Administered in Co-administration with Opioids in the Mouse Hot Plate Paradigm

In this series of experiments, non-effective doses of the compound of Example 4 were combined with subthreshold and effective doses of morphine. Compounds were co-mixed in syringes and co-administered via the intraperitoneal route 30 minutes prior to mouse heating plate paradigm as described above. A separate group of animals (n=7-8/group) was used for each dose group.

The results in Figure 2 show that the compound of Example 4 combined with subthreshold doses of morphine can produce effective antinociceptive effects. Furthermore, non-effective doses of the compound of Example 4 combined with effective doses of morphine resulted in potentiation of the antinociceptive effect.

Taken together, these results suggest that combination therapy of the disclosed compounds with opioid combinations can produce significantly enhanced analgesic effects. Conceivably, combinations of these nicotinic acetylcholine ligands with other available analgesics could also yield increased beneficial effects.

Protocol for Determination of Efficacy of Nicotinic Acetylcholine Receptor Ligands as Analgesics After Repeated Dosing in the Chung Model of Neuropathic Pain

Animals were surgically processed as described above for the preparation of the Chung model. For the evaluation of each test compound, two treatment groups (6 animals each) were established. One group was injected (i.p.) the test compound twice daily for 5 days, and the other group was similarly injected with saline. Two days before injection, 15 minutes after injection, and on day 5 of injection, the response to Von Frey hairs was evaluated for both groups as described above. The saline treated group was given saline on the first 4 days and the morning of day 5, but received a test compound challenge in the afternoon of day 5. The results for test compounds such as the compound of Example 4 and morphine are shown in Tables 3 and 4, respectively, where the white bars reflect the response before the test compound was administered and the dark bars reflect the response 15 minutes after the test compound was administered.

Significant anti-allodynia effect of the compound of Example 4 was observed in each test period, rats given the compound of Example 4 (0.3 μmol/kg, i.p.) by previous injection (twice a day) and rats given by previous injection (twice a day) Between saline rats, no difference in the antiallodynic effect stimulated with the compound of Example 4 was observed. This result indicated that the anti-allodynia effect of the compound of Example 4 was not reduced after repeated administration. In contrast, in this model, the effect of morphine (21 μmol/kg) was significantly reduced after repeated (twice daily) administration. This result indicates that the compound of Example 4 may be more useful than morphine in ameliorating chronic neuropathic pain.

Protocol for Determining the Potency of Nicotinic Acetylcholine Receptor Ligands as Analgesics for Persistent Pain in a Formalin Model

The test was carried out according to the protocol established in the literature (Tjlsen, et al., Pain, 1992, 51, 5-17). 50 μl of 5% formalin, a potent chemical irritant, was injected subcutaneously into the back of one of the hind paws of male Sprague-Dawley rats. Nociceptive behaviors in rats (such as flinching, biting, licking, or raising the paw) generally exhibit a biphasic pattern over time. Briefly, the induction period lasts about 5 minutes, followed by formalin injection, A longer response period followed, beginning approximately 20 minutes after formalin injection. The second phase response was maximal about 30-50 minutes after injection and appeared to involve an inflammatory component. During the second response period (30-50 min after formalin injection), nociceptive behavior was recorded using a time-sampling procedure (15 sec observation time per minute for each mouse). Fifteen minutes before formalin injection, rats (groups of 7) were administered test compounds at different doses. Responses were compared to similar groups receiving saline. The results in Fig. 5 show that oral administration of the compound of Example 4 produces a significant antinociceptive effect in a persistent pain model and indicates that the compound can be used as an oral analgesic for the treatment of acute pain.

Protocol for Determining the Potency of Nicotinic Acetylcholine Receptor Ligands as Analgesics in the Paw Thermal Stimulus (Hotbox) Model

For evaluation of nociceptive responses to acute thermal stimuli, commercially available paw thermal stimuli were used (Anesthesiology Research Laboratory, Department of Anesthesiology, University of California at San Diego, La Jolla, CA). This device has been described previously (Dirig, D.M. and Yaksh, T.L., Pain, 62:321-328, 1995) and is based on the initial work of Hargreaves et al. (Pain, 32:77-88, 1988). Rats were placed in Plexiglas chambers located on the glass surface of the apparatus. The glass surface was maintained at 30°C. The thermal stimulus was applied to the bottom of the rat's hind paw through a movable focused projection lamp. The stimulation current was maintained at 4.8Amps. The waiting time for the animal to remove its paw from the stimulus is automatically recorded by using a photodiode movement sensor. In this study, a cut-off time of 20 seconds was employed after exposure to the irritant to limit possible tissue damage.

All trials began with a 20-minute acclimatization period. After the acclimatization period, baseline values were determined for each animal. After determining the baseline value, treatment is administered and measurements are taken at various time points (eg, 15, 30 and 45 minutes) after treatment. For clarity, data were collected for that period of time for statistical analysis (unless otherwise indicated).

Stock solutions of compounds were prepared in absolute ethanol at a concentration of 62 μmol/ml. For this purpose, the solution was prepared in 10% ethanol and administered intraperitoneally. Compounds were tested over a dose range of 0.62-6.2 μmol/kg.

The following protocol was used to perform the assay. 6 animals were used per run. For any given measurement (eg, time point), the test is performed on a single limb of each of 6 animals, and the procedure is then repeated on the opposite limb. The mean of the responses was then calculated from the scores of the two runs.

The data from this test are presented in the table below, which show that selected compounds exhibit analgesic effects at doses of 0.62-6.2 [mu]mol/kg.

The table shows the analgesic doses of selected compounds in the Hotbox Model

Example No. Analgesic Dosage

Compounds (μmol/kg)

                                     

71 0.62

72 0.62

75 6.2

79 0.62

80 0.62

81 0.62

92 ＞6.2

95 ＞6.2

Protocol for Determining the Anti-Inflammatory Potency of Nicotinic Acetylcholine Receptor Ligands

Male Sprague-Dawley rats (Charles River, Portage, MI) weighing approximately 200 g were fasted for 16 hours with free access to water.

Sprague-Dawley rats (Charles River, Portage MI) (adrenalectomized) used for selective studies were also fasted but had free access to saline. On the day of the test, the rats were weighed and the volume of each hind paw was measured using a Buxco plethysmograph with water replacement. In these studies, all test agents were dissolved in sterile 0.9% saline and administered intraperitoneally. Upon challenge, 100 μl of 1% Carrageensis bismuth in sterile 0.9% saline was prepared according to the method described by Winter et al. (Winter, C.A., et al., Proc. Sugar solution (Sigma) was injected subcutaneously into the right hind paw. Two hours later (unless otherwise indicated), volumes of the left and right hind paws were measured to determine edema.

After the carrageenan solution was injected into the foot pads of rats, an acute inflammatory reaction occurred within the next 2-6 hours. Evidence of paw swelling was evident by direct plethysmographic measurement of paw volume. Increased paw volume is known by pressure on tendons and nerves, local inflammation, and nociceptive sensitivity (ie, pain receptors) causing hyperalgesia (ie, increased response to noxious stimuli).

The compound of Example 4 attenuated carrageenan-induced paw edema with an ED ₃₀ of 0.21 μmol/kg (ip). Furthermore, the compound of Example 4 was as effective as dexamethasone in reducing paw edema (Panel A, Figure 6). The effect of the compound of Example 4 on paw edema was blocked by the nicotinic acetylcholine receptor antagonist, mecamylamine (Panel B, Figure 6). These data demonstrate that the compound of Example 4 is active in models used to establish anti-inflammatory effects and that these effects are mediated by nicotinic acetylcholine receptors. Furthermore, as shown by the data above, compounds of formula (I) having the variables defined above in methods of treating pain should also be active in methods of reducing or treating inflammation.

These data also suggest that the compounds of the present invention are also anti-inflammatory and that the additional action of these nicotinic acetylcholine ligands to reduce inflammation may contribute to optimal pain relief.

Measurement Protocol for Cardiovascular Effects in Dogs

Male beagle dogs were anesthetized with pentobarbital (35 mg/kg, intravenously) and continuously infused with pentobarbital (5 mg/kg/h). Animals were ventilated with room air via a mechanical breathing pump. A microbarometer catheter with a duplex plug (Millar, Model SPC-770, 7F) was inserted through the carotid artery into the left ventricle to measure blood pressure. Compounds were injected through the catheter into the right femoral vein. Hemodynamic variables were calculated on a signal processing workstation (Modular Instruments, Inc.) with XYZReal Time Spreadsheet software. Six minutes after the operation, steady-state baseline values of the measured variables were obtained. Test compounds were administered by intravenous bolus and compared for their relative ability to induce changes in blood pressure and heart rate over a 5 minute data collection period.

The table shows the comparison of the cardiovascular effect of embodiment 1 and embodiment 19

Determination Example 19 Example 1

Compounds Compounds

Elevated diastolic blood pressure (mmHg) 67.3±3.2 23.2±4.6

Increased heart rate (beat/min) 26.0±7.8 7.8±2.9

The compound of Example 1 (the (R)-enantiomer of 5-(azetidinemethoxy)-2-chloropyridine) increased blood pressure only the compound of Example 19 (5-(azetidine (S)-enantiomer of butanemethoxy)-2-chloropyridine) was 1/3 of the increase in blood pressure observed. Furthermore, the compound of Example 1 increased heart rate in dogs by only 1/3 of that observed for the compound of Example 19. These data suggest that the compound of Example 1 causes less adverse effects on cardiovascular parameters than the compound of Example 19. That is, the (R)-isomer is safer than the (S)-isomer.

Transformation of prodrugs in dogs.

The prodrug form (R=ArCO, Z=Y=H, X=F) has been shown to be rapidly converted to the active drug (R=Z=Y=H, X=F) after oral administration to dogs. Data are shown in the table. In each case, peak maternal (R=H) plasma levels were observed in the range of 0.6-0.8 hr, which level (C _max ) was consistent with the effective parental dose. Conversion (F) efficiency varied between 27-61%. When these compounds were tested for the activity of nicotinic receptors (K177 cell line) in vitro, no activity was found, suggesting that the activity in vivo comes from the transformation of the R=H form.

C _max (ng/ml) T _max (hr) t1/2(hr) AUC _0-∞ F ⁺ (%)

(ng hr/ml)RhCO 6.31 0.6 1.8 18.89 27.34-NO ₂ C ₆ H ₄ CO 6.01 0.8 1.9 18.76 27.14-MeOC ₆ H ₄ CO 7.43 0.8 2.0 26.09 37.74-FC ₆ H ₄ 5-Cl 3.25 13.9 0.8 31 ₆ H ₄ CO 4.54 0.8 2.5 18.61 26.94-MeC ₆ H ₄ CO 7.05 0.8 2.4 29.85 43.14-MeO2CC ₆ H ₄ CO 10.31 0.8 1.8 42.37 61.2

⁺ Estimated bioavailability of 20 nmol/kg (R=H) given IV to dogs in each group

Beagle dogs were fasted overnight prior to dosing, but allowed free access to water. Dogs (groups of 3) were administered each prodrug at a dose of 200 nmol/kg. The formulations were administered by oral gavage. Prodrugs were prepared as 200 nmol/ml (1 ml/kg) solutions (with normal saline). Blood samples were taken from the jugular vein of each dog before dosing, and at 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6 and 8 hours after dosing. After separation of plasma from red blood cells by centrifugation, the plasma was filled onto a derivatization pre-column, followed by quantification of active drug concentration by HPLC with fluorescence detection.

Example

The following examples illustrate how specific examples were prepared from readily prepared or commercially available starting materials. The above discussion of the preparation of compounds within the scope of the present invention is also relevant to the general preparation of starting reactants for the preparation of analgesics or compounds claimed and referenced herein. The examples presented in tabular form can be readily prepared according to the methods described herein for the actual preparation of the examples. These examples are non-limiting and it is to be understood that the compounds cited herein and their uses are within the scope of the present invention.

In this section, some terms are indicated in abbreviated form. These terms are followed by abbreviations as follows:

Boc, tert-butoxycarbonyl; Cbz, benzyloxycarbonyl; DMF, N,N-dimethylformamide; MED, minimum effective dose; THF, tetrahydrofuran; TFA, trifluoroacetic acid; TLC, thin-layer chromatography; Ts, tosyl or p-toluenesulfonyl; OTs is tosylate or p-toluenesulfonate

According to the nomenclature as set forth in the Examples below, such compounds are designated as 3-pyridyl ethers with ether (O) functionality attached to the methylene-azetidinyl moiety at the 3-position of the pyridine ring. However, when the pyridyl ring is di- or poly-substituted, the actual numbering on the pyridyl ring may be changed so that, for example, the compound of formula (I) as specifically described in Example 4, wherein the chloro substituent is in the pyridine The 2-position of the base ring, while the ether linkage is at the 5-position. Those of ordinary skill in the art can readily identify these compounds.

Example 1

5-((2R)-azetidinylmethoxy)-2-chloropyridine

1a. 5-((2R)-azetidinylmethoxy)-2-chloropyridine

(R)-1-tert-butoxycarbonyl-2-azacyclyl in 195 ml of dichloromethane was treated with triethylamine (35.6 ml, 0.255 mol) followed by p-toluenesulfonyl chloride (48.5 g, 0.254 mol) Butane methanol (36.5 g, 0.195 mol) solution. The resulting mixture was stirred at room temperature for 16 hours. 10% sodium hydroxide solution was added rapidly and the mixture was stirred for 1 hour. After separation of the phases, the aqueous phase was extracted with additional dichloromethane and the combined organic phases were washed with sodium bicarbonate solution and brine, then dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 63.1 g of (R)-1-tert-butoxy Carbonyl-2-tosyloxymethylazetidine (94.8%). A solution of 2-chloro-5-hydroxypyridine (1 g, 24 g, 0.185 mol from step below) in DMF (690 ml) was then treated with triturated potassium hydroxide (17.95 g, 0.295 mol) and stirred at 80° C. for 30 minutes . (2R)-1-tert-butoxycarbonyl-2-tosyloxymethylazetidine (63.1 g) dissolved in DMF (395 ml) was quickly added to the mixture. The mixture was concentrated in vacuo to remove DMF, and the resulting residue was diluted with water and extracted with EtOAc (3X). The organic extracts were combined, dried (magnesium sulfate), filtered, and concentrated in vacuo to give 58.5 g of unpurified product. Chromatography (silica gel, 25% EtOAc in hexanes) of this material afforded 43.2 g of 5-(1-tert-butoxycarbonyl-(2R)-azetidinylmethoxy)-2-chloropyridine as Clear oil (74%). 225 ml of trifluoroacetic acid was added dropwise over 30 minutes at 0°C to treat 5-(1-tert-butoxycarbonyl-(2R)-azetidinylmethoxy)-2-chloromethane in 450 ml of dichloromethane Pyridine (30g, 0.1mol) solution. After 2 hours, the bulk of the solvent was removed in vacuo and the residue was diluted with ethyl acetate, washed with 1.0 M _K2CO3 and brine, dried ( _Na2SO4 ), and concentrated _in vacuo to give 19.1 _g of a yellow oil. Flash silica gel chromatography (90:10 chloroform:methanol, then 90:10:0.5 chloroform:methanol:ammonium hydroxide) afforded 16.5 g of the title compound (83% yield). MS (CI/NH ₃ ) m/z: 199 (M+H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ2.21-2.43 (m, 2H, 3.42-3.50 (m, 1H), 3.69-3.78 (m, ^1H ), 3.98-4.07(m, 2H), 4.25-4.34(m, ^1H ), 7.22(d, J=1.7Hz, 2H), 8.07(dd, 1.7, 2.0Hz, ^1H ) .

1b. Benzyl (R)-azetidin-2-one-4-carboxylate

To a flask containing dibenzyl(R)-aspartic acid (BACHEM, 6.5 g, 20.6 mmol) was added 82 ml of diethyl ether under nitrogen. The white heterogeneous mixture was cooled to 0° C., then 2.6 ml (2.23 g, 20.6 mmol) of chlorotrimethylsilane were added, followed by stirring for 15 minutes. Then 2.9ml (2.08g, 20.6mmol) of triethylamine was added via syringe. The resulting white heterogeneous mixture was stirred for 1 hour, then rapidly filtered through a medium fritted glass funnel filter under nitrogen flow. The cloudy white filtrate was placed under nitrogen and treated dropwise with 10.3 mL of 2M tert-butylmagnesium chloride in ether over 20 minutes. The resulting pale yellow homogeneous solution was allowed to warm slowly to room temperature overnight, then cooled to 0 °C. To this solution was slowly added 50 ml of 2N hydrochloric acid saturated with ammonium chloride. The biphasic mixture was transferred to a separatory funnel, the layers were separated, and the aqueous phase was extracted with ethyl acetate and dichloromethane. The organic extracts were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo to give 6.65g of a yellow oil which solidified on standing. The yellow solid was triturated with ethyl acetate and filtered to afford 1.7 g of benzyl (R)-azetidin-2-one-4-carboxylate as a white crystalline solid. The combined mother liquors were concentrated, triturated with ether, and filtered to give an additional 350 mg of the title compound. The combined yield is 49%. MS (CI/NH ₃ ) m/z: 206 (M+H) ⁺ , 223 (M = NH ₄ ) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ3.08 (ddd, J = 2.2, 2.8, 15.1 Hz, ^1H ), 3.34(ddd, J= ^{1.5 ,} 5.9, 15.1Hz, 1H), 4.22(dd, J=2.8, 5.9Hz, 1H), 5.21(s, 2H), 6.17(s(br ), ^1H ), 7.37(m, 5H).

Step 1c. (R)-1-(tert-butoxycarbonyl)-2-azetidinemethanol

410 mg (2 mmol) of benzyl (R)-azetidin-2-one-4-carboxylate and 10 ml of dry tetrahydrofuran were charged into a dry round bottom flask, then purged with nitrogen and cooled to 0°C. To this clear homogeneous solution was added dropwise 10 ml of 1M lithium aluminum hydride in THF via syringe. After 76 hours, the reaction was cooled to 0° C. and 400 μl of distilled water were added slowly (extensive gas evolution). The mixture was stirred for 15 minutes, then 400 μl of 15% sodium hydroxide was added, and the mixture was stirred for an additional 15 minutes. Finally, 800 μl of distilled water was added. The white heterogeneous reaction was cooled to room temperature, then filtered through a 1/2 inch plug of celite and concentrated in vacuo to give 420 mg of a pale yellow oil. A portion of this oil (310 mg) was treated with 4 ml of dichloromethane followed by 460 mg of di-tert-butyl dicarbonate (2.1 mmol). The cloudy pale yellow mixture was stirred at room temperature for 4.5 hours, then concentrated in vacuo to give 632 mg of a yellow oil. Flash silica gel chromatography (silica gel, 2:1-1:1 hexane:ethyl acetate) afforded 167 g of the title compound (61% yield). [α] _D ²⁰ +22.3 (c1.28, CHCl ₃ ); MS (CI/NH ₃ ) m/z: 188 (M+H) ⁺ ; ¹ H NMR (CDCl ₃ , 300MHz) δ1.45 (s, 9H), 1.94(m, ^1H ), 2.15(m, ^1H ), 3.68-3.92(m, 5H), 4.44(m, ^1H ).

1d. (R)-1-tert-butoxycarbonyl-2-azetidinemethanol

Another method of Example 1b-1c, according to the method of Rodebaugh, R.M. and Crmwell, N.H. (J.Heterocyclic Chem., 1969, 435) from gamma-butyrolactone to prepare (R)-1-tert-butoxycarbonyl- 2-Azetidinemethanol. In this literature method, treatment of gamma-butyrolactone with bromine and catalytic phosphorus tribromide, followed by benzyl alcohol and hydrogen chloride gas affords alpha, gamma-dibromobutyrate in 62% yield. Treat the dibromide in ethanol with 1 equivalent of benzhydrylamine and potassium carbonate at reflux for about 16 hours to give benzyl N-benzhydrylazetidine-2-carboxylate in 52 %. Hydrogenolysis with palladium hydroxide in methanol gave racemic azetidine-2-carboxylic acid in a yield of 62%. According to the method of Rodebaugh, R.M. and Cromwell, N.H. (J.Heterocyclic Chem., 1969, 993), the racemic azetidine was treated with benzyl chloroformate in aqueous sodium hydroxide solution at 0-5°C. Alkane-2-carboxylic acids are converted to N-Cbz derivatives. After isolation in quantitative yield, the N-Cbz derivative in methanol was treated with 1 equivalent of L-tyrosine hydrazide to precipitate the tyrosine acyl group of (R)-azetidine-2-carboxylic acid. Hydrazine salt, yield 77-87%. (R)-1-Cbz-azetidine-2-carboxylic acid is released from the salt by normal extraction methods. In the presence of 10% Pd/C, the methanol solution was treated with 4 atm hydrogen to hydrogenolyze the free acid for 19 hours to obtain (R)-azetidine-2-carboxylic acid, which was separated by triturating with methanol with a yield of 88%. Treatment of this product with di-tert-butyl dicarbonate and N-methylmorpholine in dioxane/water (1:1) afforded (R)-1-Boc-azetidine- 2-Carboxylic acid. The THF solution of (R)-1-Boc-azetidine-2-carboxylic acid was treated with borane-dimethylsulfide complex at room temperature for 16 hours to obtain the title compound in 92% yield.

1e.(R)-1-Benzyloxycarbonyl-2-azetidinemethanol

The title compound was prepared from D-methionine according to the method of Sugano and Miyoshi, Bull. Chem. Soc. Japan, 1973, 46, 669 . D-methionine (29.84g, 200mmol) was dissolved in water (100ml), and 1N sodium hydroxide (200ml, 200mmol) was added to obtain a homogeneous solution. Cool if necessary to maintain a temperature of about 20°C and add p-toluenesulfonyl chloride (53.4 g, 280 mmol). 1N NaOH was added in small portions over 2 hours as needed to maintain the pH at about 9 (total amount about 280 mL), and the mixture was stirred at room temperature overnight. The mixture was acidified to pH 3-4 with 4.5N hydrochloric acid and then stored at -20°C. White crystals (26.1 g, 43%) were collected. Another isolated fraction was harvested as an amber oil which was collected and dried in vacuo to yield 24.8 g (41%). NMR and MS (m/z 321, (M+NH4) ⁺ ) of both harvests were consistent with pure N-p-toluenesulfonyl-D-methionine. The combined yields of N-p-toluenesulfonyl-D-methionine (53.5 g, 176 mmol) were dissolved in HOAc (53 ml), 88% HCO ₂ H (106 ml) was added, followed by methyl iodide (20 ml), and the mixture was Leave to stand overnight in the dark. The volatile components were evaporated under reduced pressure and the residue was triturated repeatedly with diethyl ether to give a semi-solid residue which was dissolved in 1N sodium hydroxide (180ml). The solution was maintained at 90°C for 3 hours while maintaining pH 6-7 by addition of 3N sodium hydroxide. The solution was acidified to pH 2-3 with 3N hydrochloric acid, and the white precipitate was collected by filtration and dried to give 28 g of α-(N-p-toluenesulfonyl-amino)-γ-butyrolactone. Additional yield was obtained from the mother liquor stored at -20°C to give another 8.3 g of product (combined yield 81%), mp 132-134°C. MS: m/z 273, (M+ _NH4 ⁺ ), 291M+( _NH4 ) ₂ ) ⁺ . According to the method of Miyoshi, et al. (Chem. Lett. 1973, 5-6), (R)-α-(N-tosylamino)-γ-butyrolactone (20 g) in ethanol (150 ml) The suspension was maintained at 65°C while bubbling hydrogen bromide (g) into the mixture. After the mixture became homogeneous, hydrogen bromide sparging was continued at 65°C slowly to maintain maximum saturation throughout the reaction. The volatile components were evaporated and the residue was chromatographed (silica gel, 30% ethyl acetate/hexanes) to give 17.8 g (about 65%) of (R)-N-p-toluenesulfonyl-γ-bromonorvaline Ethyl ester, as pale yellow oil. MS: (Cl/NH ₃ ) m/z 301 (M-HBr+NH ₄ ) ⁺ , 381 (M+NH ₄ ) ⁺ ; M+(NH ₄ ) ₂ ) ⁺ . To N-p-toluenesulfonyl-γ-bromonorvaline ethyl ester (24.24g, 66.5mmol) in DMF (725ml) was added water (3.64ml) followed by 60% sodium hydride (8g). The mixture was stirred at 10-20°C for 20 minutes, after which time the mixture was acidified with 1N hydrochloric acid, the solvent was evaporated, followed by addition of dichloromethane and evaporation twice. 10% hydrochloric acid was added to precipitate the product, which was collected and recrystallized from ethyl acetate/petroleum ether to obtain 12.3 g (72%) of (R)-N-p-toluenesulfonylazetidine-2-carboxylic acid, White flocculent crystals: mp 144-145°C; [α] _D +146 (c0.61, CHCl ₃ ); MS (CI/NH ₃ ) m/z: 273 (M+NH ₄ ). Further manipulations were performed as described by Abreo et al. (J. Med. Chem. 1996, 39, 817-825). Analysis of enantiomeric purity was performed by conversion to α-methylbenzylamine and evaluated by ¹ H NMR, indicating an approximately 4:1 mixture of enantiomers. This mixture (1.48 g, 5.8 mmol) was slurried in liquid ammonia (25 mL) at -78 °C. Sodium metal was added until a dark blue color persisted for 30 minutes, then solid ammonium chloride was added until the blue color disappeared. To evaporate the ammonia, a water bath was used instead of a cold bath. The remaining white solid was carefully dissolved in water (30ml) and HOAc to adjust the pH of the mixture to 7.0. Then 1,4-dioxane (30ml) and N-(benzyloxycarbonyloxy)succinimide (2.1g, 8.7mmol) were added and the mixture was stirred for 2 hours. The biphasic mixture was partitioned and partitioned between saturated potassium carbonate and diethyl ether. _The aqueous phase was acidified with 12N hydrochloric acid, then extracted with _CH2Cl2 . The organic phase was dried (magnesium sulfate), concentrated, and chromatographed (chloroform:methanol:HOAc, 95:5:0.5) to give a colorless oil (955 mg, 70%): MS (CI/ _NH3 ) m/z: 236 (M+H) ⁺ ; ¹ H NMR (CDCl ₃ , 300MHz) δ2.47-2.60(m, 2H), 3.98-4.07(m, 2H), 4.78-4.87(m, ^1H ), 5.65(s, 2H), 7.28-7.40 (m, 5H). The resulting 1-benzyloxycarbonylazetidine-2-carboxylic acid (932 mg, 3.96 mmol) was dissolved in methanol (20 ml), and L-tyrosine hydrazide (773 mg, 3.96 mmol) was added. The slurry was heated at reflux for 10 minutes, allowed to cool to room temperature, then filtered. The filter cake was dissolved in 6M hydrochloric acid and extracted with EtOAc (2X). The organic fractions were combined, dried (magnesium sulfate) and concentrated to give (R)-1-benzyloxycarbonylazetidine-2-carboxylic acid as a colorless oil (403 mg, 55%): [α] _D ²⁰ +104.7 (c4.0, _CHCl3 ). (R)-1-benzyloxycarbonylazetidine-2-carboxylic acid (2.0 g, 8.6 mmol) in THF (35 ml) was cooled to 0°C and 1.0 MBH ₃ ·THF (12.9 ml , 12.9 mmol). The mixture was allowed to warm to room temperature and stirred for 2.5 hours. 2N hydrochloric acid solution was added carefully. The heterogeneous mixture was stirred for 1 hour. The slurry was extracted with dichloromethane, the organic phase was dried (magnesium sulfate), concentrated, and chromatographed (silica gel, ethyl acetate/hexane, 1:1) to give the title compound (1.46 g, 77%) as a colorless oil : [α] _D ²⁰ 15.5 (c1.2, CHCl ₃ ). MS (CI/NH ₃ ) m/z: 222 (M+H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ1.93-2.08 (m, ¹ H), 2.18-2.29 (m, ¹ H), 3.72-4.01 (m, 4H), 4.47-4.58 (m, ^1H ), 5.12 (s, 2H), 7.30-7.41 (m, 5H).

1f.5-Acetoxy-2-chloropyridine

At -10°C, boron trifluoride etherate (76.5ml, 0.662mol) was slowly added to 5-amino-2-chloro in a solution of pyridine (40.0 g, 0.311 mol, Aldrich). A solution of tert-butyl nitrite (44.4 mL, 0.373 mol) in 40 mL of 1,2-dimethoxyethane was then added slowly over 15 minutes to maintain the reaction temperature below -5°C. The mixture was stirred at -10°C for 10 minutes, then warmed to 0°C and stirred for an additional 30 minutes. Pentane was added and the solid was collected by suction filtration (cold heptane wash) to yield 69.1 g of diazonium tetrafluoroborate. This was dissolved in 350 ml of acetic anhydride, warmed to 75°C (nitrogen evolution) and stirred for 3 hours. The volatiles were removed in vacuo and the dark residue was diluted with ether and washed with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ether. The combined ether extracts were washed with brine, dried (magnesium sulfate) and concentrated, and purified by chromatography (silica gel, hexane/ethyl acetate, 90:10-70:30) to give the title compound (29.4 g, 55 %): mp 45°C; ¹ H NMR (CDCl ₃ , 300 MHz) δ: 2.35 (s, 3H), 7.35 (d, J = 8.5 Hz, ¹ H), 7.48 (dd, J = 2.9, 8.5 Hz, ¹ H), 8.21 (d, J=2.9Hz, ¹ H); MS (CI/NH ₃ ) m/z: 172, 174 (M+H) ⁺ ; 189, 191 (M+NH ₄ ) ⁺

1g.2-Chloro-5-hydroxypyridine

5-Acetoxy-2-chloropyridine from Example If (11.1 g, 64.7 mmol) was dissolved in methanol at room temperature and solid potassium carbonate (4.47 g, 32.4 mmol) was added. After stirring for 2 hours, the volatiles were removed in vacuo and the residue was diluted with ether and water. The aqueous phase was adjusted to pH 7 by adding 1N aqueous hydrochloric acid. The layers were separated and the aqueous phase was extracted twice with ether. The combined organic extracts were dried (magnesium sulfate) and concentrated to give the title compound (8.03 g, 96%) as a white solid: mp 155 °C; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.20-7.28 (m, 2H), 7.88 (m, ¹ H); MS (CI/NH ₃ ) m/z: 130, 132 (M+H) ⁺ ; 147, 149 (M+NH ₄ ) ⁺ .

Example 2

5-((2R)-azetidinylmethoxy)-2-chloropyridine p-toluenesulfonate

To the flask containing 5-((2R)-azetidinylmethoxy)-2-chloropyridine (750 mg, 3.78 mmol) from Example 1 was added 15 ml of absolute ethanol followed by p-toluene Sulfonyl monohydrate (718 mg, 3.78 mmol, Aldrich). The mixture was stirred at room temperature for 15 minutes, then concentrated in vacuo. The off-white crystalline solid was triturated with ethyl acetate, filtered and placed in a vacuum oven overnight (ca. 16 hours, ca. 15 mmHg) to afford the title compound (1.38 g, 99%) as a white crystalline solid: mp 158-161 °C; [α] _D ²⁰ +5.4°(c1.05, MeOH); ¹ H NMR (DMSO-d ₆ , 300MHz) δ8.88 (s(br), 2H), 8.19 (d, J=2.9Hz, ¹ H), 7.46- 7.58(m, 4H), 7.11(d, J=7.0Hz ^1H ), 4.73(m, ^1H ), 4.42(dd, J=7.0, 11.4Hz, ^1H ), 4.33(dd, J=3.3, 11.4Hz, ^1H ); 3.86-3.97(m, 2H), 2.35-2.55(m, 2H); MS(CI/ _NH3 ) m/z: 199(M+H) ⁺ ; 216(M+ _NH4 ) ⁺ .

Example 3

5-((2R)-azetidinylmethoxy)-2-chloropyridine benzoate

To the flask containing 5-((2R)-azetidinylmethoxy)-2-chloropyridine (780 mg, 3.93 mmol) from Example 1 was added 16 ml of absolute ethanol and purged with nitrogen. To this solution was added benzoic acid (480 mg, 3.93 mmol). After 1 hour, the mixture was concentrated in vacuo to give a viscous yellow oil. The oil was treated with 10 mL of diethyl ether with stirring for 10 minutes to give a fine white crystalline precipitate. The solid was filtered off and washed with ether, and placed in a vacuum oven (about 20°C, about 15 mmHg) overnight to give the title compound (1.1 g, 88%): mp 102-104°C; [α] _D ²⁰ +5.35°(c1 .03, MeOH); ¹ H NMR (CDCl ₃ , 300MHz) δ8.02 (d, J=2.7Hz, ¹ H), 7.92 (m, 2H), 7.33-7.50 (m, 5H), 7.10 (m, 2H), 4.64(m, 2H), 4.23(m, 2H), 3.91(m, 2H), 2.44-2.65(m, 2H); MS(CI/NH ₃ ) m/z: 199(M+H) ⁺ ; 216(M+NH ₄ ) ⁺ .

Example 4

5-((2R)-azetidinylmethoxy)-2-chloropyridine hydrochloride

5-((2R)-azetidinylmethoxy)-2-chloropyridine (478mg, 2.4mmol) from Example 1 was slurried in diethyl ether (100ml) at room temperature Ether saturated with HCl was added slowly until no more solids precipitated out. The solvent was removed and the yellow solid was recrystallized from methanol/ether to give the title compound (365 mg, 64%) as a fine white powder: mp 116-117°C; MS (CI/NH ₃ ) m/z: 199/201 (M+ H) ⁺ ; ¹ H NMR (D ₂ O, 300MHz) δ2.65-2.76(m, 2H), 4.03-4.21(m, 2H), 4.42(d, J=4.1Hz, 2H), 4.92-5.00( m, ¹ H), 7.47 (d, J=8.8 Hz, ¹ H), 7.56 (dd, J=3.0 Hz, ¹ H), 8.15 (d, J=3.0 Hz, ¹ H). _Anal. Calcd. for _C9H12Cl2N2O : C, 45.98; H, 5.14 _; N, 11.91; Found: C _, 46.03; H, 5.06; N, 11.76. [α] _D ²⁰ +8.6 (c0.52, MeOH).

Example 5

5-((2R)-azetidinylmethoxy)-2-chloropyridine dihydrochloride

Into a flask containing 5-((2R)-azetidinylmethoxy)-2-chloropyridine (25.0 g, 0.126 mol) from Example 1 in dichloromethane at 0° C. An excess of HCl saturated ether solution was added. After the addition was complete, the white heterogeneous mixture was concentrated in vacuo. Recrystallization from methanol and ether afforded the title compound (30.5 g, 89%) as a white hygroscopic solid: mp 113-115; [α] _D ²⁰ +11.8 (c 0.84, MeOH); ¹ H NMR (D ₂ O , 300MHz) δ2.65-2.76(m, 2H), 4.03-4.21(m, 2H), 4.42(d, J=4.1Hz, 2H), 4.95(m, ^1H ), 7.47(d, J=8.8 Hz, ¹ H), 7.56 (dd, J=3.0 Hz, 8.8 Hz, ¹ H), 8.15 (d, J=3.0 Hz, ¹ H). _Anal . Calcd. for _C9H13Cl3N2O : C, 37.78; H, 4.72 _; N, 9.79; Found: C _, 37.50; H, 4.70; N, 9.55.

Example 6

(R)-3-(2-azetidinylmethoxy)pyridine dihydrochloride

Diethyl azodicarboxylate (1.2ml, 7.9mmol) was added to a stirred solution of triphenylphosphine (2.1g, 7.9mol) in THF (60ml) at 0°C. After 15 minutes, (R)-1-(benzyloxycarbonyl)-2-azetidinemethanol (1.46 g, 6.6 mmol, step 1e above) in THF (6.6 ml) was added to the reaction vessel, 3-Hydroxypyridine (690 mg, 7.3 mmol, Aldrich) was then added. After stirring at room temperature for 18 hours, the solvent was removed and the residue was dissolved in dichloromethane, washed with saturated potassium carbonate, dried (magnesium sulfate), concentrated and chromatographed (silica gel, EtOAc/hexanes, 1:2) to give ( R)-1-(benzyloxycarbonyl)-3-((2-azetidinylmethyl)oxy)pyridine and triphenylphosphine oxide mixture (2.8 g): MS (CI/NH ₃ ) m/z: 299 (M+H) ⁺ . A sample (1.6 g) of this mixture was dissolved in ethanol (25 ml) and stirred under one atmosphere of hydrogen (1 atm) in the presence of 10% Pd/C (320 mg) for 4 hours. The reaction was filtered, concentrated and chromatographed (silica gel, chloroform:methanol:ammonium hydroxide 90:10-90:10:0.5) to afford the free base of the title compound as an amber oil (465 mg, 75% overall yield). [α] _D ²⁰ +5.8 (c1.6, CHCl ₃ ); MS (CI/NH ₃ ) m/z: 165 (M+H) ⁺ ; ¹ H NMR (CDCl ₃ , 300MHz) δ2.22-2.46 ( m, 2H), 3.45-3.51(m, ^1H ), 3.73(dd, J=7.7, 8.5Hz, 1H), 4.00-4.10(m, 2H), 4.26-4.35(m, ^1H ), 7.21- 7.24 (m, 2H), 8.22 (dd, J = 2.9, 3.0 Hz, ¹ H), 8.33 (dd, J = 1.5, 2.2 Hz, ¹ H). (R)-3-((2-Azetidinylmethyl)oxy)pyridine (450 mg, 2.74 mmol) was slurried in diethyl ether (20 ml) and methanol (ca. Diethyl ether saturated with hydrogen chloride gas was added at the same time. The solvent was removed and the residue was recrystallized from methanol/ether to give a hygroscopic white solid (206 mg, 31%): mp 138-140°C; [α] _D ²⁰ +9.8 (c0.5, MeOH). MS (CI/NH ₃ ) m/z: 165 (M+H) ⁺ ; ¹ H NMR (D ₂ O, 300 MHz) δ2.71 (dd, J=8.5, 17.3 Hz, 2H), 4.05-4.21 (m , 2H), 4.57(d, J=4.4 Hz, 2H), 4.96-5.03(m, ^1H ), 7.99(dd, J=5.7, 9.0Hz, ^1H ), 8.21(ddd, J=1.2, 2.8 , 9.0Hz, ^1H ), 8.46(d, J=5.7Hz, 1H), 8.59(d, J=2.8Hz, 1H); Anal. Calcd. for C ₉ H ₁₂ N ₂ O·2HCl·0.2H ₂ O : C, 44.90; H, 6.03; N, 11.64; Found: C, 44.90; H, 5.98; N, 11.54.

Example 7

(S)-3-(2-azetidinylmethoxy)pyridine dihydrochloride

7a. (S)-3-((2-azetidinylmethyl)oxy)pyridine dihydrochloride

An ice-cold solution of 1-butoxycarbonyl-2-(S)-azetidinemethanol (2.8 g, 15.0 mmol, Step 7C below) in THF (40 mL) was stirred under nitrogen. To this solution was added DEAD (3.54ml, 22.46mmol), followed by triphenylphosphine (4.78g, 22.5mmol), and the mixture was stirred for 10 minutes. 3-Hydroxypyridine (2.14g, 22.5mmol) and further tetrahydrofuran (40ml) were then added to the reaction. After stirring for 18 hours, additional 3-hydroxypyridine (0.10 g, 1.05 mmol) was added and the reaction was stirred for an additional 24 hours. When all the starting azetidinol was consumed, the reaction mixture was concentrated in vacuo. The crude mixture was then acidified (pH<2) with 10% potassium bisulfate solution (80ml) and washed with ethyl acetate (3 x 75ml). The aqueous portion was then basified (pH = 10) with saturated potassium carbonate solution and the product was extracted with ethyl acetate (4 x 75ml). These extracts were dried (magnesium sulfate), filtered and concentrated in vacuo to a reddish brown oil (1.84 g, 50% yield). Purification by flash silica gel chromatography with Rf=0.19 (ethyl acetate:hexane, 2:1) gave the coupled product as a light yellow oil with a yield of 25%; MS (CI/NH ₃ ) m/z: 265 (M +H) ⁺ , 282 (M+NH ₄ ) ⁺ ; ¹ H NMR (CDCl ₃ ) δ8.36-8.35 (dd, J=3.7Hz, J=0.7Hz, ¹ H), 8.24-8.22 (dd, J =4.0Hz, J=1.5Hz, ^1H ), 7.25-7.22(m, 2H), 4.56-4.48(m, ^1H ), 4.36-4.31(dd, J=10Hz, J=4.9Hz, ^1H ) , 4.17-4.12(dd, J=10Hz, J=2.9Hz, ^1H ), 3.92-3.87(dd, J=8.2, J=6.8Hz, ^1H ), 2.42-2.25(m, 2H), 1.42(s , 9H). To an ice-cold solution of the above compound (286mg, 1.08mmol) in absolute ethanol (4ml) was added a hydrogen chloride-saturated ethanol solution (4ml) under nitrogen. The reaction mixture was stirred for 18 hours while gradually warming to room temperature, then the reaction mixture was concentrated in vacuo and the product was dissolved in absolute ethanol and triturated with diethyl ether. The pure title compound was obtained by two recrystallizations from ethanol and ether as a white powder (174 mg, 87 mmol, 81% yield): mp 135-137°C; [α] _D -5.0 (c0.4, MeOH). MS(CI/NH ₃ ) m/z: 165(M+H) ⁺ ; 182(M+NH ₄ ) ⁺ ; ¹ H NMR(D ₂ O, 300MHz) δ8.60-8.59(d, J=2.9Hz , ¹ H), 8.48-8.46(d, J=5.8Hz, ¹ H), 8.25-8.21(ddd, J=9.0Hz, J=2.6Hz, J=1.1Hz, ¹ H), 5.05-4.97(m , ¹ H), 4.59-4.57 (d, J=4.0Hz, 2H), 4.22-4.05 (m, 2H), 2.77-2.67 (dd, J=16.9Hz, J=8.45Hz, 2H); C ₉ H _Anal. Calcd. _{for12N2O.2.7HCl.0.2H2O} : C, _40.60 ; H, 5.71; N, 10.52; Found: C, 40.75; H, 5.76;

7b. 1-Butoxycarbonyl-2-(S)-azetidinecarboxylic acid

To an ice-cold solution of 2-(S)-azetidinecarboxylic acid (10.2 g, 100 mmol, Aldrich) in 300 ml of 1:1 water/1,4-dioxane was added di-tert-butyl dicarbonate (28.5 g, 131 mmol), followed by 4-methylmorpholine (11.7 g, 115 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then poured into ice-cold saturated sodium bicarbonate solution (250ml) and washed with ethyl acetate. The aqueous phase was acidified (pH=1) with potassium hydrogensulfate and the product was extracted with ethyl acetate. These organic extracts were dried (sodium sulfate), filtered and concentrated in vacuo to give the title compound as a white semi-solid: MS (CI/NH ₃ ) m/z: 202 (M+H) ⁺ , 219 (M+NH ₄ ) ⁺ ; ¹ H NMR (CDCl ₃ , 300MHz) δ10.0 (br, s, ¹ H), 4.81-4.76 (t, J=15Hz, ¹ H), 3.99-3.83 (m, 2H), 2.62-2.38 (m, 2H), 1.48 (s, 9H).

7c. 1-tert-butoxycarbonyl-(2S)-azetidinemethanol

To a solution of the compound from step 7b (9.39g, 46.7mmol) in THF (100ml) was added borane-THF complex (IM, 210ml, 4.50eq) under nitrogen. The reaction mixture was gradually warmed to room temperature and stirred for 48 hours. 10% Aqueous potassium bisulfate solution (60ml) was added gradually and the volatile components were evaporated in vacuo. The remaining slurry was extracted with ethyl acetate. The organic extracts were washed with saturated aqueous sodium bicarbonate, dried (magnesium sulfate), filtered and concentrated in vacuo to provide the title compound (8.4 g, 96%) as a colorless oil. MS (CI/NH ₃ ) m/z: 188 (M+H) ⁺ ; ¹ H NMR (CDCl ₃ , 300MHz) δ4.49-4.40 (ddd, J=9.0Hz, J=9.0Hz, J=3.0Hz , ₁ H), 3.95-3.68 (m, 4H), 2.23-2.12 (m, ₁ H), 1.99-1.87 (m, ₁ H), 1.46 (s, 9H).

Example 8

5-(2R)-azetidinylmethoxy)-2-fluoropyridine dibenzoate

8a. 5-(2R)-azetidinylmethoxy)-2-fluoropyridine dibenzoate

A solution of diethyl azodicarboxylate (4.7ml, 3.0mmol) was added to a solution of triphenylphosphine (0.80g, 3.0mmol) in THF (20ml) at 0°C, and the mixture was stirred for half an hour. Then 1-(tert-butoxycarbonyl)-2-(R)-azetidinemethanol (0.51 g, 2.7 mmol, obtained from Example 1c above) and 2-fluoro-5-hydroxypyridine ( 0.32g, 2.8mmol, step 8e) below. The mixture was allowed to warm slowly to room temperature and stirred overnight. The solvent was removed and the residue was chromatographed (silica gel, hexane/EtOAc, 9:1 to 7:3) to provide 0.80 g of coupled product: MS (CI/NH ₃ ) m/z: 283 (M+H) ⁺ , 300 (M+NH ₄ ) ⁺ ; ¹ H NMR (CDCl ₃ , 300MHz) δ1.42(m, 9H), 3.33(m, ^1H ), 3.89(t, J=7.31Hz, 1H), 4.11(m, ^1H ), 4.31(m, ^1H ), 4.51(m, ^1H ), 6.85(m, ^1H ), 7.38(m, ^1H ), 7.87(m, ^1H ). 6-Fluoro-3-(1-tert-butoxycarbonyl)-2-(R)-azetidinemethoxy)pyridine (760 mg, 2.70 mmol) was mixed with dichloromethane ( 2 ml) in TFA (2 ml) and the solution was stirred for 30 minutes. Volatiles were removed in vacuo. The residue was basified with saturated aqueous sodium bicarbonate and extracted with dichloromethane. Drying (magnesium sulfate) and concentration of the organic extracts and chromatography of the residue (silica gel, dichloromethane:methanol:ammonium hydroxide 10:1:0.1) afforded the free base of the title compound (240mg, 49%). The base was converted to the dibenzoate salt by treatment with benzoic acid in ether to give the title compound (235 mg, 42%): mp 76-80°C; [α] _D 2.9 (cl, MeOH). MS (CI/NH ₃ ) m/z: 183 (M+H) ⁺ ; ¹ H NMR (D ₂ O, 300 MHz) δ 2.23 (m, ¹ H), 2.34 (m, ¹ H), 3.49 (m , ^1H ), 3.66 ⁽ m, ^1H ), 4.14(m, ^1H ), 4.35(m, 1H), 7.12(dd, J=2.44, 8.81Hz, ^1H ), 7.45(m, 4H) , 7.56 (m, 2H), 7.63 (m, ¹ H), 7.93 (m, 3H); Anal. Calcd. for C ₉ H ₁₁ N ₂ OF·2C ₆ H ₅ COOH: C, 64.78; H, 5.44; N , 6.57; Found: C, 64.65; H, 5.48; N, 6.45.

8b. 2-Fluoro-5-nitropyridine

2-Chloro-5-nitropyridine (100g, 0.656mol, Aldrich), potassium fluoride (84.1g, 1.45mol, Aldrich), tetraphenylphosphonium bromide (95.3g, 0.227mol, Aldrich) and acetonitrile (1.5 L) were mixed and heated at reflux until the 2-chloro-5-nitropyridine was completely consumed. The volume of the mixture was reduced to 750ml, diluted with 2L of ether, filtered and concentrated. The resulting residue was triturated with hot hexane and the combined hexane extracts were concentrated to give the title compound (48 g, 54%): ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.15 (dd, J=3, 6 Hz, ¹ H ), 8.64 (m, ¹ H), 9.15 (d, J=1.6 Hz, ¹ H).

8c. 3-Amino-6-fluoropyridine

2-Fluoro-5-nitropyridine (52.4 g, 368 mmol, from step 8b above) was mixed with 5% Pd/C (100 mg, Aldrich) in ethanol (100 ml) and the mixture was stirred under hydrogen 4 sky. The mixture was filtered and concentrated. The crude product was chromatographed (silica gel, hexane/ethyl acetate, 9:1-1:1) to obtain 30.9 g (75%) of the title compound: ¹ H NMR (DMSO-d ₆ , 300 MHz) δ6.74 (dd , J=3.6HzH, ^1H ), 7.11(m, ^1H ), 7.26(t, J=1Hz, ^1H ), MS(CI/NH ₃ ) m/z: 113(M+H) ⁺ , 130 (M+NH ₄ ) ⁺ .

8d. 3-Acetoxy-6-fluoropyridine

A solution of 3-amino-6-fluoropyridine (5.0 g, 45 mmol, from step 8c above) in DMF (30 ml) was added to a cooled (-15 °C) solution of boron trifluoride (12.2 ml, 99 mmol) middle. Tert-butyl nitrite (6.3ml, 54mmol) was then added at a rate to maintain the temperature below 0°C. , the reaction was placed at -10°C for 10 minutes, then warmed to 5°C and stirred for 30 minutes. Pentane (150ml) was added to the reaction mixture and the resulting solid was collected by suction filtration, washed with cold diethyl ether, air dried and dissolved in 75ml of acetic anhydride. The solution was heated to 105°C until nitrogen evolution ceased. The solvent was removed in vacuo, the residue was suspended in saturated aqueous sodium carbonate (200ml) and extracted with diethyl ether (2 x 150ml). Dry (magnesium sulfate) and concentrate the combined organic extracts. Purification by chromatography (silica gel, hexane/ethyl acetate, 9:1-7:3) gave the title compound (2.25 g, 33%): ¹ H NMR (CDCl ₃ , 300 MHz) δ2.32 (s, 3H) , 6.96 (d, J=3, 9Hz, ¹ H), 7.59 (m, ¹ H), 8.03 (dd, J=0.5, 1Hz, ¹ H); MS (CI/NH ₃ ) m/z: 156 ( M+H) ⁺ , 171(M+NH ₄ ) ⁺

8e. 2-Fluoro-5-hydroxypyridine

5-Acetoxy-2-fluoropyridine (2.26 g, 14.6 mmol, from Step 8d above) was dissolved in 20% aqueous sodium hydroxide (15 mL). After stirring at room temperature for 2 hours, the solution was neutralized by adding concentrated hydrochloric acid. The aqueous mixture was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and the solvent was evaporated. Purification by chromatography (silica gel, chloroform/methanol, 98:2) afforded 1.31 g (79%) of the title compound: MSm/z: 114 (M+H) ⁺ , 131 (M+NH ₄ ) ⁺ ; ¹ H NMR ( CDCl ₃ , 300 MHz) δ6.84 (dd, J=1.85, 5.14 Hz, ¹ H), 7.43 (m, ¹ H), 7.81 (t, J=2.84 Hz, ¹ H).

Example 9

5-(2S)-Azetidinylmethoxy)-2-fluoropyridine dibenzoate

According to the method of Example 8, replace its 1-tert-butoxycarbonyl-2-(R)-azetidine with 1-tert-butoxycarbonyl-2-(S)-azetidinemethanol Alkanemethanol, preparation of the title compound: mp76-80°C; MS (CI/NH ₃ ) m/z: 183 (M+H) ⁺ ; ¹ H NMR (D ₂ O, 300MHz) δ2.65 (m, 2H), 4.11(m, 2H), 4.38(d, J=4.39, 2H), 4.92(m, ^1H ), 7.09(dd, J=2.83, 9.28Hz, ^1H ), 7.50(m, 4H), 7.56( m, 2H), 7.63 (m, ¹ H), 7.92 (m, 4H); Anal. Calcd. for C ₉ H ₁₁ N ₂ OF·2C ₆ H ₅ CO ₂ H: C, 64.78; H, 5.44; N, 6.57; Found: C, 64.55; H, 5.46; N, 6.59.

Example 10

5-((2S)-azetidinylmethoxy)-3-fluoropyridine dihydrochloride

10a. 5-((2S)-azetidinylmethoxy)-3-fluoropyridine dihydrochloride

A solution of 3-fluoro-5-hydroxypyridine (500 mg, 4.43 mmol, from step 10f below) in dimethylformamide (20 ml) was treated with triturated potassium hydroxide (400 mg, 7.10 mmol) and stirred at 80 °C 30 minutes. Dissolve 1-(tert-butoxycarbonyl)-(2S)-p-toluenesulfonyloxymethylazetidine (1.05g, 4.39mmol) in dimethylformamide (5ml) as follows 10b) was quickly added to this mixture and the reaction mixture was stirred at 80°C for 16 hours. The mixture was concentrated to remove dimethylformamide and the resulting residue was diluted with water and extracted with EtOAc (3X). The organic extracts were combined, dried (magnesium sulfate), filtered and concentrated in vacuo. This material was purified by flash chromatography (silica gel, hexane/ethyl acetate, 10:1) to give 5-fluoro-3-(1-tert-butoxycarbonyl-(2S)-azetidinemethoxy ) pyridine (692 mg, 56%): ¹ HNMR (CDCl ₃ , 300 MHz) δ 1.40 (s, 9H), 2.30 (m, 2H), 3.92 (m, 2H), 4.16 (m, ¹ H), 4.40 ( m, ¹ H), 4.54 (m, ¹ H), 7.05 (m, ¹ H), 8.20 (m, 2H); MS (CI/NH ₃ ) m/z: 283 (M+H) ⁺ . HCl/ether in dichloromethane was added to the above 5-fluoro-3-(1-Boc-(2S)-azetidinemethoxy)pyridine (320 mg, 1.14 mmol) at 0°C, The solution was stirred for 2 hours. The solvent was removed and the residue was recrystallized from EtOH/ether to give the title compound (250 mg): mp 165-167°C; [α] _D ²⁵ 27.8 (c 0.56, MeOH). ¹ H NMR (D ₂ O, 300MHz) δ2.70(m, 2H), 4.10(m, 2H), 4.50(d, J=4.5Hz, 2H), 5.01(m, ^1H ), 7.80(tt, J=3Hz, ^1H ), 8.42 (dd, J=3, 6Hz, 2H); MS (CI/NH ₃ ) m/z: 183 (M+H) ⁺ , 200 (M+NH ₄ ) ⁺ .

10b. (S)-1-tert-butoxycarbonyl-2-toluenesulfonyloxymethylazetidine

A solution of (2S)-1-tert-butoxycarbonyl-2-azetidine in methanol (22.6 g, 0.121 mol) in 40 mL of pyridine was treated with p-toluenesulfonyl chloride (27.6 g, 0.145 mol). The resulting mixture was stirred at room temperature for 16 hours. Dilute with dichloromethane, then wash successively with 1N aqueous hydrochloric acid, water, saturated aqueous potassium carbonate and brine, dry (sodium sulfate) and concentrate the organic phase. Purification by chromatography (silica gel; hexane/ethyl acetate, 80:20) gave 32.8 g of a white solid, which was recrystallized from dichloromethane/ethane to give the title compound as white needles: mp 59-60°C ; ¹ H NMR (CDCl _3- , 300MHz) δ1.37(m, 9H), 2.15-3.28(m, 2H), 2.44(s, 3H), 3.74-3.81(m, 2H), 4.13(dd, J =3.1, 10.2Hz, ^1H ), 4.23-4.34(m, 2H), 7.35(d, J=8.1Hz, 2H), 7.80(d, J=8.2Hz, 2H). MS (CI/ _NH3 ) m/z: 242 (M+H) ⁺ .

10c. 3-Benzyloxy-5-bromopyridine

Sodium hydride (60% in mineral oil) (40.9 g, 1.0225 mol) in 800 ml DMF was cooled to 0°C and benzyl alcohol (105 ml, 1.014 mol) was added slowly. The reaction mixture was stirred at 20°C for 1 hour, then 3,5-dibromopyridine (200.4 g, 846 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated ammonium chloride (500ml), diluted with water and extracted with ether. The combined ether extracts were washed with 50% brine and dried (magnesium sulfate). The solvent was evaporated in vacuo, and the crude product was recrystallized from diethyl ether to give the title product (161 g, 72%): mp 63-68°C; ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.37-8.27 (m, 2H), 7.5-7.35 ( m, 6H), 5.1 (s, ¹ H); MS (CI/NH ₃ ) m/z: 264, 266 (M+H) ⁺ .

10d.3-Amino-5-benzyloxypyridine

The product of the above Example 10c (41.3g, 156mmol), cuprous (I) bromide (22.43g, 156mmol), methanol (275ml) and liquid ammonia (50ml) were mixed in a stainless steel reactor and heated to 130°C for 24 Hour. The mixture was allowed to cool to room temperature, then concentrated. The residue was suspended in 300 ml saturated aqueous sodium carbonate and extracted with dichloromethane. The combined dichloromethane solutions were washed with brine, dried (magnesium sulfate), and concentrated. The crude product was chromatographed (silica gel; hexane/ethyl acetate, 9:1-7:3) to give the title compound (15.6 g, 50%): ¹ H NMR (CDCl ₃ , 300 MHz) δ: 8.21-8.29 (m , 2H), 7.44-1.26 (m, 6H), 5.10 (s, 2H); MS (CI/NH ₃ ) m/z: 201 (M+H) ⁺ .

10e.3-fluoro-5-benzyloxypyridine

The product of Example 10d (10 g, 50 mmol) dissolved in DMF (100 ml) was added under nitrogen to a solution of boron trifluoride etherate (9.3 ml, 75 mmol) cooled to -15 °C to maintain the temperature Tert-butyl nitrite (7.8ml, 65mmol) was added at a rate below -5°C. , after 10 minutes at -10°C the reaction was warmed to 5°C and stirred for 30 minutes. Pentane (200ml) was added to the reaction mixture and the solid was collected by suction filtration, washed with cold diethyl ether, then dissolved in acetic anhydride (150ml) and the resulting solution was heated to 70°C until nitrogen evolution ceased. The solvent was removed in vacuo, the residue was suspended in saturated aqueous sodium carbonate and extracted with ether. The ether solution was dried (sodium sulfate) and concentrated. The crude product was chromatographed (silica gel, hexane/ethyl acetate, 6:1) to obtain 2.0 g of the title compound: ¹ H NMR (CDCl ₃ , 300 MHz) δ5.17 (s, 2H), 7.04 (tt, J=3Hz , ¹ H), 7.41 (m, 5H), 8.15 (d, J=3Hz, ¹ H), 8.25 (d, J=3Hz, ¹ H); MS (CI/NH ₃ ) m/z: 204 (M +H) ⁺ , 221(M+NH ₄ ) ⁺

10f.3-fluoro-5-hydroxypyridine

The product from Example 10e (2.0 g, 9.85 mmol) was stirred under hydrogen atmosphere in the presence of 10% Pd/C (50 mg) for 4 hours, the mixture was filtered and concentrated to afford 1.1 g (93%) of the title as a white solid Compound: ¹ H NMR (300MHz) δ7.78(tt, J=3Hz, ¹ H), 8.38(d, J=3Hz, ¹ H), 8.56(d, J=3Hz, ¹ H), 10.72(b, ¹ H); MS (CI/NH ₃ ) m/z: 114 (M+H) ⁺ , 131 (M+NH ₄ ) ⁺ .

Example 11

5-((2R)-azetidinylmethoxy)-3-fluoropyridine dibenzoate

According to the method of Example 10a, replace 1-tert-butoxycarbonyl-2-(S)-p-toluenesulfonyloxymethylazetidine with the corresponding (R)-isomer (Example 1c) Alkane, the free amine compound (65%) was obtained: ¹ H NMR (CDCl ₃ , 300MHz) δ1.42 (s, 9H), 2.30 (m, 2H), 3.92 (m, 2H), 4.16 (dd, J=3Hz , ¹ H), 4.38(m, ¹ H), 4.58(m, ¹ H), 7.05(tt, J=3Hz, ¹ H), 8.20(dd, J=3Hz, ¹ H); MS(CI/NH ₃ ) m/z: 283 (M+H) ⁺ . HCl/ether in dichloromethane was added to the above 5-(N-Boc-(2R)-azetidinemethoxy)-3-fluoropyridine (692 mg, 2.45 mmol) at 0°C. The solvent was removed and the residue was recrystallized from ethanol/ether to give the title compound (365 mg): mp 163-165°C; [α] _D ²⁵ -30.0 (c0.51, MeOH). ¹ H NMR (D ₂ O, 300 MHz) δ 2.72 (m, 2H), 4.15 (m, 2H), 4.52 (d, J=4.5, 2H), 4.98 (m, ¹ H), 7.40 (d, J =12 Hz, ¹ H), 8.42 (b, 2H); MS (CI/NH ₃ ) m/z: 183 (M+H) ⁺ , 200 (M+NH ₄ ) ⁺ . _Anal. Calcd. for _C9H12FClN2O - _0.3HCl : C, 47.08; H, 5.40; N, 12.20; Found: C, 47.25; H, 4.90; N, 12.04.

Example 12

5-((2S)-azetidinylmethoxy)-3-bromopyridine dihydrochloride

12a. 5-((2S)-azetidinylmethoxy)-3-bromopyridine dibenzoate

Triphenylphosphine (4.01 g, 15.3 mmol) and DEAD (2.43 ml, 15.3 mmol) were dissolved in 30 ml THF at 0° C., and the mixture was stirred for 10 minutes. Add 1-tert-butoxycarbonyl-2-(S)-azetidinemethanol (2.86 g, 15.3 mmol, step 7c above) and 3-bromo-5-hydroxypyridine (1.51 g, 10.2 mmol, above Step 10c), the mixture was stirred at room temperature for 40 hours. The volatile components were removed in vacuo, the residue was triturated with hexane, the separated hexane fraction was concentrated, and the residue was chromatographed (silica gel, hexane/ether, 10:1-10:2) to give 5-bromo-3-( (1-tert-butoxycarbonyl)-(2S)-azetidinyl)(methoxy)pyridine as a colorless oil (1.669 g): ¹ H NMR (CDCl ₃ , 300 MHz) δ1. 42(s, 9H), 2.31( ^{m, 2H), 3.89(m, 2H), 4.12(m, 1H), 4.322(m, 1H )} , 4.52(m, ^1H ), 7.43(m, ¹ H), 8.92 (m, 2H) MS (CI/NH ₃ ) m/z: 344 (M+H) ⁺ . Treatment of 5-bromo-3-(2-(1-BOC-2-(S)-azetidinyl)methoxy)pyridine with 4M HCl in dioxane gave the free base of the title compound . This was converted to the dihydrochloride salt and recrystallized from methanol/ether to afford the title compound: mp 163-165°C; [α] _D ²⁵ -5.1 (c 0.57, methanol). ¹ H NMR (D ₂ O, 300MHz) δ8.36 (d, J=1.8Hz, ¹ H), 8.32 (d, J=2.6Hz, ¹ H), 7.84 (dd, J=1.8, 2.6Hz, ¹ H), 4.98-4.90 (m, ¹ H), 4.43 (d, J=4.0Hz, 2H), 4.20-4.02 (m, 2H), 2.67 (q, J=8.5Hz, 2H); MS (CI/ NH ₃ ) m/z: 243/246 (M+H) ⁺ , 260/262 (M+NH ₄ ) ⁺ . _Anal. Calcd. for _{C9H13N2OBrCl2} : C, 34.21; H, 4.15; _{N ,} 8.86; Found: C, 34.18; H, 4.17; N, 8.89.

12b. 3-Bromo-5-hydroxypyridine

3-Benzyloxy-5-bromopyridine from Example 10c was heated with 48% HBr/HOAc (60 mL) at reflux for 16 hours. The reaction was quenched with excess sodium bicarbonate, the basic mixture was extracted with ethyl acetate, and the extract was dried over sodium sulfate. The solvent was removed, and the residue was chromatographed (silica gel, methanol/carbon tetrachloride, 1/10) to obtain the title compound: ¹ H NMR (CDCl ₃ , 300MHz) δ8.27 (d, J=1.8Hz, ¹ H), 8.23 (d, J = 2.6Hz, ¹ H), 7.44 (dd, J = 1.8, 2.6 Hz, ¹ H); MS (CI/NH ₃ ) m/z: 174, 176 (M+H) ⁺ , 191 , 193(M+NH ₄ ) ⁺ .

Example 13

5-Methyl-3-((2S)-azetidinylmethoxy)pyridine dibenzoate

5-Bromo-3-(1-tert-butoxycarbonyl)-(2S)-azetidinylmethoxy)pyridine (400 mg, 1.20 mmol, Step 12a above) in THF ( 10 ml) solution was added a catalytic amount of [1,3-bis(diphenylphosphino)-propane]nickel(II) chloride (3.8 mg) followed by MeMgBr (0.8 ml, 3.0 M in THF, Aldrich). The mixture was refluxed for 3 hours, cooled to room temperature, quenched with saturated aqueous ammonium chloride, evaporated to remove volatile components, and the residue was dissolved in dichloromethane and saturated aqueous ammonium chloride. The organic extracts were dried over magnesium sulfate and concentrated. Chromatography (silica gel; dichloromethane/methanol, 10:0.2-10:0.5) of the residue afforded 5-methyl-3-(1-tert-butoxycarbonyl)-(2S)-azetidinyl Methoxy)pyridine, as an oil (177 mg, 53%): ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.42 (m, 9H), 2.20-2.40 (m, 2H), 3.90 (t, J=8.33 Hz, 2H), 4.14(m, ^1H ), 4.31(m, ^1H ), 4.51(m, ^1H ), 7.04(s, ^1H ), 8.06(s, ^1H ), 8.18(d, J = 3.33 Hz, ¹ H); MS (CI/NH ₃ ) m/z: 279 (M+H) ⁺ . TFA (10ml) was added to a solution of the above product (170mg, 0.6mmol) in dichloromethane (2ml) at 0°C. After stirring for 30 minutes, it was basified with 15% aqueous sodium hydroxide and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated. Chromatography (silica gel; dichloromethane/methanol, 10:1) of the crude product afforded 5-methyl-3-(azetidinyl-(2S)-methoxy)pyridine as an oil (93 mg, 64%): ¹ H NMR (CDCl ₃ , 300MHz) δ 2.28 (m, ¹ H), 2.36 (s, 3H), 2.39 (m, ¹ H), 3.43 (m, ¹ H), 3.65 (q, J=3.33Hz, ^1H ), 3.98-4.02(m, 2H), 4.22(m, ^1H ), 7.12(m, ^1H ), 8.04(s, ^1H ), 8.14(d, J=3.33Hz , ¹ H); MS (CI/NH ₃ ) m/z: 179 (M+H) ⁺ . The above product was slurried in ether and HCl in ether was added dropwise. The solvent was removed and the resulting solid was recrystallized from methanol/ether to give the title compound as a pale yellow hygroscopic solid: ¹ H NMR (D ₂ O, 300 MHz) δ 2.36 (s, 3H), 2.67 (q, J =8.33Hz, 2H), 4.04-4.21(m, 2H), 4.40(d, J=3.40Hz, 2H), 4.90(m, ^1H ), 7.40(s, ^1H ), 8.04(s, ^1H ), 8.14(s, ¹ H). MS (CI/ _NH3 ) m/z: 179 (M+H+) ⁺ . _Anal. Calcd. _{for C10H14N2O.1.5HCl} : C, 51.57; H, 6.71; N, 12.03; Found: C, 51.53; H, 6.86; N, 12.03.

Example 14

5-Methyl-3-((2R)-azetidinylmethoxy)pyridine hydrochloride

Following the procedure of Example 12a, substituting 1-tert-butoxycarbonyl(2R)-azetidinemethanol (from Example 1d) for its 1-tert-butoxycarbonyl)-(2S)-nitrogen Hetidinemethanol, preparation of 5-bromo-3-(1-tert-butoxycarbonyl)-(2R)-azetidinylmethoxy)pyridine. According to the method of Example 13, replace its 5-bromo- 3-(1-tert-butoxycarbonyl)-(2S)-azetidinylmethoxy)pyridine, the title compound was prepared as a white solid: [α] _D -5.38 (c0.93, MeOH). ¹ H NMR (D ₂ O) δ 2.40(s, 3H), 2.70(q, 2H, J=9.30Hz), 4.04-4.20(m, 2H), 4.42(d, 2H, J=5.0Hz), 4.95-5.00 (m, ¹ H), 7.45 (s, ¹ H), 8.08 (s, ¹ H), 8.15 (s, ¹ H); MS (CI/NH ₃ ) m/z: 179 (M+H ) ⁺ , 196(M+NH ₄ ) ⁺ . _{Anal. Calcd} . for _{C10H14N2O.1.5HCl} : C, 51.57; H, 6.71; N, 12.03; Found: C, 51.53; H, 6.86; N, 12.03.

Example 15

5-((2S)-azetidinylmethoxy)-2,3-dichloropyridine hydrochloride

15a. 5-((2S)-azetidinylmethoxy)-2,3-dichloropyridine hydrochloride

A solution of triphenylphosphine (2.6g, 9.94mmol) and diethyl azodicarboxylate (1.6ml, 9.94mmol) in THF (16ml) was stirred at 0°C for 15 minutes. Add 1-tert-butoxycarbonyl-2-(S)-azetidinemethanol (1.55 g, 8.28 mmol, from step 7c above) and 5,6-dichloro-3-pyridinol (1.5 g, 9.1 mmol). The reaction mixture was slowly warmed to room temperature and stirred overnight at room temperature. The solvent was removed and the residue was redissolved in dichloromethane. The solution was washed with saturated aqueous potassium carbonate, dried (magnesium sulfate) and concentrated. The residue was chromatographed (silica gel, ethyl acetate/hexane, 1:5) to give 5,6-dichloro-3-(1-tert-butoxycarbonyl-2-(S)-azetidinemethanol Oxy)pyridine (1.08g): MS (CI/NH ₃ ) m/z: 333 (M+H) ⁺ ; ¹ H NMR (CDCl ₃ , 300MHz) δ1.42 (s, 9H), 2.22-2.42 ( m, 2H), 3.85-3.92(m, 2H), 4.12(dd, J=2.7, 10.1Hz, ^1H ), 4.30-4.40(m, ^1H ), 4.48-4.56(m, ^1H ), 7.41 (d, J = 2.8 Hz, ¹ H), 7.97 (d, J = 2.8 Hz, ¹ H). Add 5,6-dichloro-3-(1-tert-butoxycarbonyl-2-(S)-azetidinemethoxy)-pyridine (1.06g, 3.11mmol) in dichloromethane at 0°C (10ml) solution was added TFA (10ml). The solution was allowed to warm to room temperature and stirred for 45 minutes, and the volatile components were removed in vacuo. The residue was treated with saturated potassium carbonate solution and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and concentrated. The residue was chromatographed (silica gel, methanol: chloroform: ammonium hydroxide, 1:10:0-1:10:0.05) to give the free base of the title compound (475 mg, yield 64%): mp59-60°C; MS ( CI/NH ₃ ) m/z: 233 (M+H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.21-2.44 (m, 2H), 3.45 (m, ¹ H), 3.73 (dd, J =8.4, 15.8Hz, ^1H ), 3.98-4.08(m, 2H), 4.28(m, ^1H ), 7.37(d, J=2.8Hz, ^1H ), 8.01(d, J=2.8Hz, ¹ h). The base (336 mg) was slurried in ether and converted to the hydrochloride salt by treatment with saturated HCl in ether. The title compound (317 mg, yield 81%) was obtained by recrystallization from methanol/ether: mp 181-182°C; MS (CI/NH ₃ ) m/z: 233 (M+H) ⁺ ; ¹ H NMR (D ₂ O, 300MHz) δ2.65-2.74(m, 2H), 4.03-4.21(m, 2H), 4.44(d, J=4.4Hz, ^1H ), 4.95(m, ^1H ), 7.79(d, J = 2.9 Hz, ¹ H), 8.13 (d, J = 2.9 Hz, ¹ H). _Anal. Calcd. _{for C9H11N2OCl2-1.0 HCl} : C, 40.10; H, 4.11; N, 10.39; Found: C, 39.89; H, 4.08; N, 10.25.

15b.5-Amino-2,3-dichloropyridine

Following the method of Koch and Schnatterer (Synthesis, 1990, 499-501). An aqueous solution (300 ml) of potassium carbonate (21.4 g, 0.18 mol) was added dropwise to 2-hydroxy-5-nitropyridine (70.0 g, 0.5 mol) in 12N hydrochloric acid at a rate to maintain the temperature below ≤ 60°C . The mixture was stirred at about 50°C for 30 minutes, then cooled to room temperature and then further cooled on an ice bath. The yellow solid was collected by filtration, washed with cold water, and dried under vacuum at 50 °C to give 3-chloro-2-hydroxy-5-nitropyridine (72.4 g, 83%) as a yellow powder. To phosphorus oxychloride (37.4ml, 0.4mol) was added quinoline (23.6ml, 0.2mol) at 0°C, followed by 3-chloro-2-hydroxy-5-nitropyridine (70g, 0.4 mol). The mixture was heated at 120°C for 2.5 hours, at which point the mixture became a dark liquid. After cooling to 100°C, water (150ml) was added carefully and the mixture was cooled to 0°C. The precipitated solid was collected by filtration, washed with cold water, and dried under vacuum at 50°C to give 2,3-dichloro-5-nitropyridine (68.6 g, 89%). Iron metal was added to 2,3-dichloro-5-nitropyridine (68.5 g, 0.39 mol) in a mixture of water (800 ml) and acetic acid (160 ml) with stirring until the starting material was consumed (TLC analysis ). The mixture was filtered and the filter cake was washed repeatedly with ethyl acetate. The aqueous filtrate was extracted with ethyl acetate, and the organic portions were combined and concentrated. The residue was chromatographed (silica gel, methanol/chloroform, 0.5:99.5-1:99) to give the title compound (44.5 g, 70%) as a light orange powder: MS (CI/NH ₃ ) m/z: 163 and 165(M+H) ⁺ , 180 and 182(M+NH ₄ ) ⁺ .

15c.5-Ethoxy-2,3-dichloropyridine

A solution of the compound of Example 15b (10.0 g, 61.3 mmol) in dimethoxyethane (20 ml) was added to a flask containing boron trifluoride etherate (11.3 ml, 91.9 mmol) at -15°C middle. A solution of tert-butyl nitrite (8.7ml, 73.5mmol) in dimethoxyethane (61ml) was then added at a rate to maintain the internal temperature below -5°C. The mixture was stirred at 5°C for 0.75 hours, then pentane (200ml) was added. The mixture was filtered, and the filter cake was washed with cold ethyl acetate, then dried to give 15.0 as a light orange solid. The material was gradually heated to 70°C in the presence of acetic anhydride and held at this temperature until gas evolution ceased, and then held for another half hour. The mixture was cooled to room temperature, concentrated in vacuo, then diluted with ether. The solution was washed with water, then dried (magnesium sulfate) and concentrated. Chromatography (silica gel, ethyl acetate/hexanes, 1:9) of the residue afforded the title compound (9.2 g, 73%) as a clear yellow oil: MS (CI/NH ₃ ) 206 and 208 (M+ H ⁺ ).

15d. 5,6-dichloro-3-pyridinol

The product from Example 15c (9.15g, 44.4mmol) was treated with 2N potassium hydroxide solution (67ml, 133mmol) and the mixture was stirred for 18 hours. The mixture was diluted with water and treated with acid to pH 6-7. The solid precipitate was collected by filtration, washed with water, and dried at 50°C to give 5.4 g (94%) of the title compound as a white solid: MS (CI/NH ₃ ) 164, 166, 168 (M+H ⁺ ).

Example 16

5-((2R)-azetidinylmethoxy)-2,3-difluoropyridine hydrochloride

Following the procedure of Example 15a, replacing 1-Boc-(2S)-azetidinemethanol with 1-tert-butoxycarbonyl-(2R)-azetidinemethanol (3mmol) (step 1d) , preparation of the title compound (212 mg, 83% yield): mp 166-168 °C; [α] ²⁵ _D 9.5 (c0.55, MeOH); MS (CI/NH ₃ ) m/z: 233, 235, 237 ( M+H) ⁺ ; ¹ H NMR (D ₂ O, 300MHz) δ2.65-2.74 (m, 2H), 4.03-4.20 (m, 2H), 4.44 (d, J=4.4Hz, ¹ H), 4.91 -5.00 (m, ¹ H), 7.79 (d, J = 2.7 Hz, ¹ H), 8.13 (d, J = 2.7 Hz, ¹ H); Anal. Calcd. for C ₉ H ₁₁ N ₂ OCl ₂ ·1.0 HCl : C, 40.10; H, 4.11; N, 10.39; Found: C, 40.01; H, 4.02; N, 10.33.

Example 17

5-((2S)-azetidinylmethoxy)-3-bromo-2-chloropyridine hydrochloride

Triphenylphosphine (2.52g, 9.6mmol) was added to a solution of diethyl azodicarboxylate (1.52ml, 9.6mmol) in THF (56ml) at 0°C, and the reaction mixture was stirred for half an hour. Then 1-tert-butoxycarbonyl-(2S)-azetidinemethanol (1.44 g, 7.7 mmol, step 7c) and 5-bromo-6-chloropyridin-3-ol (1.4 g, 6.4 mmol; prepared from 2-hydroxy-5-nitropyridine according to the method of V. Koch and S. Schnatterer (Synthesis, 1990, 499-501). The mixture was allowed to warm slowly to room temperature and stirred overnight. The solvent was removed and the residue was chromatographed (silica gel, chloroform/methanol, 100:1) to provide 5-bromo-6-chloro-3-(1-tert-butoxycarbonyl-2-(S)-azepine Cyclobutanylmethoxy)pyridine: MS (CI/NH ₃ ) m/z: 377, 379 (M+H) ⁺ . TFA was added to a solution of the above product (360mg, 0.95mmol) in dichloromethane at 0°C, and the mixture was stirred for 30 minutes. Volatiles were removed in vacuo. The residue was neutralized with sodium bicarbonate, then extracted with dichloromethane. Dried over magnesium sulfate and concentrated. Chromatography (silica gel, dichloromethane:methanol:ammonium hydroxide 10:1:0.1) of the residue afforded the free base of the title compound. The base was converted to the title compound (224 mg) by treatment with hydrogen chloride in ether: mp 168-169 °C; [α] ²⁵ _D -4.81 (c 0.13, MeOH); ¹ H NMR (D ₂ O, 300 MHz )δ2.69 (dd, J=7.0, 8.5, 2H), 4.06-4.20 (m, 3H), 4.43 (d, J=4.5, 2H), 4.95 (m, ^1H ), 7.94 (d, J= 3.0, ¹ H), 8.17 (d, J=3.0, ¹ H); MS (CI/NH ₃ ) m/z 277, 279 (M+H ⁺ ). _Anal. Calcd. for _{C9H10N2OBrCl.0.9HCl :} C, 34.83; H, 3.54; N, 9.03; Found: C, 34.85; H, 3.56; N, 8.82.

Example 18

5-((2R)-azetidinylmethoxy)-3-bromo-2-fluoropyridine hydrochloride

A solution of triphenylphosphine (1.10 g, 4.20 mmol) and diethyl azodicarboxylate (0.65 ml, 4.2 mmol) in THF (10 ml) was stirred at 0° C. for half an hour, followed by addition of (R)-aza Cyclobutanol (0.6 g, 3.2 mmol, from step 1d above) and 5-bromo-6-chloropyridin-3-ol (0.80 g, 3.8 mmol; prepared as in Example 17) in THF (5 ml) . The mixture was allowed to warm to room temperature over 24 hours, then concentrated. The residue was triturated with a hexane/ether mixture and filtered to remove triphenylphosphine oxide. The filtrate was concentrated and the crude product was chromatographed (silica gel, hexane/ethyl acetate, 60:40) to provide 5-(1-tert-butoxycarbonyl-(2R)-azetidinylmethoxy)- 3-Bromo-2-chloropyridine as an oil (1.10 g, 91%). The product from above was then dissolved in dichloromethane (30ml) and cooled at 0°C. TFA (excess) was added and the mixture was allowed to warm to room temperature over 1 h. The solution was concentrated, and saturated sodium carbonate solution (30ml) was added, followed by extraction with diethyl ether and dichloromethane. The combined organic extracts were dried (sodium sulfate) and concentrated to give the free base of the title compound (0.83 g, 100%). A solution containing the base (0.34g, 1.2mmol) was dissolved in dichloromethane (10ml) and cooled to 0°C, followed by the dropwise addition of ethereal HCl until the mixture became cloudy. The solvent was removed and the product was recrystallized from ethanol/dichloromethane/ether to give the title compound (0.34 g, 81%) as a white solid: mp 175°C; [α] _D ²³ 7.2 (c0.5, MeOH); ¹ H NMR (D ₂ O, 300MHz) δ2.65-2.73(q, 2H), 4.03-4.20(m, 2H), 4.43(d, J=4.2Hz, 2H), 4.92-4.98(m, ^1H ), 7.93 (d, J=2.7 Hz, ¹ H), 8.17 (d, J=2.7 Hz, ¹ H); MS (CI/NH ₃ ) m/z 277 (M+H ⁺ ). _Anal. Calcd. for _{C9H11Cl2BrN2O} - _0.1H2O : C, 34.23; H, 3.57; N, _{8.87 ;} Found: C, 34.26; H, 3.36; N, 8.68.

Example 19

5-((2S)-azetidinylmethoxy)-2-chloropyridine dihydrochloride

According to the method of Example 12a, 950 mg (5.1 mmol) of 1-tert-butoxycarbonyl-2-(S)-azetidine methanol sample (prepared as in Example 7c above) and 550 mg (4.25 mmol) of 2- Chloro-5-hydroxypyridine (1 g in Example above) was added to a solution of triphenylphosphine and DEAD (5.1 mmol each) in 20 ml THF to yield 1.09 g of 3-(1-tert-butoxycarbonyl-(2S)- Azetidinylmethoxy)-6-chloropyridine: [α] _D ²⁵ -67.3 (c1.1, CHCl ₃ ); ¹ H NMR (DMSO-d ₆ , 300MHz) δ8.14 (d, J=3.3Hz, ^1H ), 7.48(dd, J=8.8, 3.3Hz, 1H) ^, 7.37(d, J=8.8Hz, ^1H ), 4.47-4.42(m, ^1H ), 4.36(dd , ^J =11.0, 4.4Hz, ^1H ), 4.20(dd, J=11.0, 3.3Hz, 1H), 3.77(t, J=7.7Hz, 2H), 2.36-2.29(m, ^1H ), 2.19 -2.12 (m, ¹ H), 1.36 (s, 9H); MS (CI/NH ₃ ) m/z: 299/301 (M+H) ⁺ . A portion of this material (1.02G) was stirred with 10ml of 4.5N hydrochloric acid for 30 minutes at room temperature. The solvent was removed and the product was recrystallized from methanol/ether to give 340 mg of the title compound: mp 113-115°C; ¹ H NMR (D ₂ O, 300 MHz) δ 8.15 (d, J=3.0 Hz, ¹ H), 7.57 (dd , J=8.9, 3.0Hz, ^1H ), 7.47(d, J=8.9Hz, ^1H ), 4.98-4.89(m, ^1H ), 4.42(d, J=4.4Hz, 2H), 4.19-4.02 (m, 2H), 2.68 (q, J = 8.5 Hz, 2H); MS (CI/NH ₃ ) m/z: 299/301 (M+H) ⁺ . _{Anal. Calcd} . for _C9H13N2OCl3 : C, 39.80; H, 4.82; N, _10.32 ; Found: C, 40.12; H, 4.84; N, 10.35.

Example 20

5-((2S)-azetidinylmethoxy)-2-picoline dihydrochloride

An ice-cold solution of the compound from Example 7c (0.232 g, 1.24 mmol) was reacted with 5-hydroxy-2-methylpyridine (Aldrich, 0.142 g, 1.30 mmol) under the conditions of Example 15a and purified on silica gel ( Ethyl acetate/hexanes 2:1) gave 2-methyl-5-(1-tert-butoxycarbonyl-(2S)-azetidinemethoxy)pyridine (0.123 g, 36%). MS (CI/NH ₃ ) m/z: 279 (M+H) ⁺ ; ¹ H NMR (CDCl ₃ , 300MHz) δ8.22 (d, J=2.6Hz, ¹ H), 7.20 (dd, J=8.5 , 3.0Hz, ¹ H), 7.08(d, J=8.5Hz, ¹ H), 4.50(m, ¹ H), 4.29(m, ¹ H), 4.13(dd, J=9.9, 2.9Hz, ¹ H ), 3.89 (t, J=7.75Hz, 2H), 2.51 (s, 3H), 2.37-2.28 (m, 2H), 1.41 (m, 9H). This material (0.12 g, 0.44 mmol) was treated with saturated ethanolated HCl (5 mL) for 18 hours. The volatiles were removed in vacuo, the solid was washed with ether, evaporated to dryness and recrystallized (ethanol/ether) to give the title compound (0.074 g, 63%) as ^a white solid: mp 141-144°C; [α] _D24- 7.89 (c0.19, MeOH); MS (CI/NH ₃ ) m/z 179 (M+H ⁺ ); ¹ H NMR (D ₂ O, 300 MHz) δ8.33 (d, J=2.9 Hz, ¹ H ), 7.89(dd, J=9.0, 2.8Hz, ^1H ), 7.64(d, J=8.8Hz, ^1H ), 4.97(m, ^1H ), 4.48(d, J=4.4Hz, 2H), 4.21-4.04 (m, 2H), 2.70 (q, J=8.5Hz, 2H), 2.62 (s, 3H); Anal. Calcd. for C ₁₀ H ₁₆ Cl ₂ N ₂ O·0.5H ₂ O: C, 44.62 ; H, 6.74; N, 10.41; Found: C, 44.55; H, 7.02; N, 10.50.

Example 21

5-((2S)-azetidinylmethoxy)-3-chloropyridine dihydrochloride

An ice-cold solution of the compound from Example 7c (0.242 g, 1.20 mmol) was reacted with 5-chloro-2-hydroxypyridine (0.187 g, 1.40 mmol) under the conditions of Example 15a and chromatographed (silica gel, Ethyl acetate/hexane 2:1) to give 5-((1-tert-butoxycarbonyl-2-(S)-azetidine)methoxy)-3-chloropyridine (0.137g, 88%). MS (CI/NH ₃ ) m/z: 299 (M+H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ8.25 (d, J=1.38 Hz, ¹ H), 8.21 (br.s, ¹ H), 7.29(t, J=2.2Hz, ^1H ), 4.52(m, ^1H ), 4.34(m, ^1H ), 4.13(dd, J=10.3, 2.9Hz, ^1H ), 3.91-3.86 (m, 2H), 2.51 (s, 3H), 2.38-2.29 (m, 2H), 1.43 (s, 9H). A portion of this material (0.13 g, 0.44 mmol) was treated with saturated ethanolated HCl (5 mL) for 16 hours. The volatiles were removed in vacuo and the solid was recrystallized from ethanol/ether to give the title compound (0.094 g, 80%) as a white solid: mp 156-157°C; [α] _D ²³ -3.23° (c 0.16, MeOH) ; MS (CI/NH ₃ ) 199 (M+H ⁺ ), 216 (M+NH ₄ ) ⁺ . ¹ H NMR (D ₂ O, 300MHz) δ8.41(d, J=5.1Hz, ¹ H), 8.39(d, J=4.4Hz, ¹ H), 7.94(t, J=2.1Hz, ¹ H) , 4.97(m, ¹ H), 4.50(d, J=4.0Hz, 2H), 4.20-4.03(m, 2H), 2.69(q, J=8.45Hz, 2H); C ₉ H ₁₃ Cl ₃ N ₂ Anal. Calcd. for _O.0.5H2O : C, 38.53; H, 5.03; N, 9.98; Found: C, 38.51; H, 5.16; N, 9.96.

Example 22

5-vinyl-3-((2S)-azetidinylmethoxy)pyridine dihydrochloride

5-Bromo-3-(2-(1-tert-butoxycarbonyl-2-(S)-azetidinemethoxy)pyridine (1.37 g, 3.99 mmol, Step 12a above) was mixed with vinyltributyltin (1.44ml, 4.79mmol), tetrakis(triphenylphosphine)palladium(0) (140mg, 0200mmol). The mixture was stirred overnight at 100°C, cooled to room temperature, and the volatiles were removed in vacuo Purification by chromatography (silica gel, hexane:ethyl acetate 5:1-1:1) afforded the vinyl substituted pyridine as an oil (1.06 g, 92%): MS (CI/NH ₃ ) m/z 291 (M+H ⁺ ); ¹ H NMR (CDCl ₃ , 300MHz) δ1.40 (s, 9H), 2.30-2.42 (m, 2H), 3.87 (t, J=7.72Hz, 2H), 4.11 (dd , J=2.94, 9.92Hz, ^1H ), 4.35(m, ^1H ), 4.53(m, ^1H ), 5.80(d, J=12.67Hz, ^1H ), 5.83(d, J=19.33Hz, ¹ H), 6.68 (dd, J=12.67, 19.33Hz, ¹ H), 7.29 (t, J=2.67Hz, ¹ H), 8.24 (d, J=3.30, ¹ H). Let some of the The material (191mg, 0.66mmol) was dissolved in dichloromethane (2ml) and TFA (1.8ml) was added. After stirring for 30 minutes, the solution was basified with 15% aqueous sodium hydroxide solution and extracted with dichloromethane. Dried over magnesium sulfate The combined organic extracts were concentrated. Purification by chromatography (silica gel, dichloromethane:methanol:ammonium hydroxide 10:0.4-10:1:0.3) afforded the free amine of the title compound as an oil (101 mg, 81%) L : MS (CI/NH ₃ ) m/z 191 (M+H ⁺ ); ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.44-2.56 (m, 2H), 3.72 (m, ¹ H), 3.88 (m, ^1H ), 4.16(m, 2H), 4.54(m, ^1H ), 5.40(d, J=11.03Hz, ^1H ); 5.82(d, J=17.65Hz, ^1H ), 6.66(dd, J =11.0, 17.65Hz, ¹ H), 7.26 (m, ¹ H), 8.18 (d, J=3.33Hz, ¹ H), 8.22 (d, J=1.67Hz, ¹ H). The amine was dissolved in ether Slurry and add 1.0M HCl in ether dropwise. Volatiles were removed and the title compound was obtained by recrystallization from methanol/ether as a yellow hygroscopic powder: mp 88-90°C; [α] _D ²³ +2.58° (c0.62, MeOH); MS (CI/NH ₃ ) m/z: 191 (M+H) ⁺ ; ¹ H NMR (D ₂ O, 300MHz) δ2.64-2.76 (m, 2H), 4.044. 20(m, 2H), 4.49(d, J=4.1Hz, 2H), 4.96(m, ^1H ), 5.58(d, J=11.0Hz, ^1H ), 6.04(d, J=17.7Hz, ¹ H), 6.83(dd, J=11.0Hz, J=17.7Hz, ^1H ), 7.85(t, J=1.9Hz, ^1H ), 8.33(d, J=14.3, ^1H ); C ₁₁ H _{14 Anal.} Calcd. for N2O.1.8HCl: C, 51.64; H, 6.22; N, 10.95; Found: C, 51.59; H, 5.92;

Example 23

5-Ethyl-3-((2S)-azetidinylmethoxy)pyridine dihydrochloride

5-(N-tert-butoxycarbonyl-(2S)-azetidinemethoxy)-3-bromopyridine (1.37g, 3.99mmol, step 12a above) in toluene (30ml) was mixed with Vinyltributyltin (1.44ml, 4.79mmol), tetrakis(triphenylphosphine)palladium(0) (140mg, 0.20mmol) were combined. The reaction mixture was stirred at 100°C for 16 hours. The solvent was removed under reduced pressure, and the resulting residue was chromatographed (silica gel, hexane:ethyl acetate 5:1-1:1) to obtain 3-vinyl-5-(N-tert-butoxycarbonyl-(S)- Azetidine-2-methoxypyridine as an oil (1.06 g, 92%): MS (CI/NH ₃ ) m/z 291 (M+H ⁺ ); ¹ H NMR (CDCl ₃ , 300 MHz )δ1.40(s, 9H), 2.30-2.42(m, 2H), 3.87(t, J=7.7Hz, 2H), 4.11(dd, J=2.9, 9.9Hz, ^1H ), 4.35(m, ¹ H), 4.53(m, ¹ H), 5.80(d, J=12.7Hz, ¹ H), 5.83(d, J=19.3Hz, ¹ H), 6.68(dd, J=12.6, 19.3Hz, ¹ H), 7.29 (t, J = 2.7Hz, ¹ H), 8.24 (d, J = 3.3Hz, ¹ H). 5% Pt (54 mg, Aldrich) and 3-vinyl on carbon at room temperature - A suspension of 5-(1-tert-butoxycarbonyl-(2S)-azetidinemethoxypyridine (540mg, 1.87mmol) in methanol (10ml) was placed under hydrogen for 16 hours. The catalyst was removed by filtration and The solvent was concentrated to give 3-ethyl-5-(N-tert-butoxycarbonyl-(2S)-azetidine-2-methoxypyridine as an oil (480 mg, 88%): MS (CI /NH ₃ ) m/z 293 (M+H ⁺ ); ¹ H NMR (CDCl ₃ , 300MHz) δ1.25 (t, J=8.3Hz, 3H), 1.42 (s, 9H), 2.20-2.40 (m , 2H), 2.64(q, J=8.3Hz, 2H), 3.88(t, J=8.3Hz, 2H), 4.12(dd J=3.3, 8.0Hz, ^1H ), 4.32(m, ^1H ), 4.51(m, ^1H ), 7.08(t, J=3.3Hz, ^1H ), 8.08(d, J=1.7Hz, ^1H ), 8.16(d, J=2.3Hz, ^1H ). At 0℃ To a solution of the product from above (479mg, 1.64mmol) in dichloromethane (6ml) was added TFA (5.5ml). After 30 minutes, the solution was basified with 15% aqueous sodium hydroxide and extracted with dichloromethane (3X) The organic extract was dried over magnesium sulfate, filtered and concentrated. Purification by chromatography (silica gel, dichloromethane:methanol:ammonium hydroxide 10:0.4:0-10:1:0.3) gave the free base of the title compound as an oil Compound (228mg, 72%): MS (CI/NH ₃ ) m/z 193 (M+H ⁺ ); ¹ HNMR (CDCl ₃ , 300MHz) δ1.24 (t, J=8.3Hz, 3H), 2.20- 2.48(m, 2H), 2.62(q, J=8.3Hz, 2H), 3.46-3.54(m, 2H), 3.64(q, J=8.7Hz, ^1H ), 4.06(t, J=5.7Hz, 2H), 7.16(t, J=2.7Hz, ^1H ), 8.07(d, J=1.7Hz, ^1H ), 8.13(d, J=3.3Hz, ^1H ). The free amine was dissolved in ether and HCl in ether was carefully added dropwise. The solvent was then removed and the salt recrystallized from methanol/ether to afford the title compound as a white hygroscopic solid: [α] _D ²⁵ +3.85° (c3.64, MeOH); MS (CI/NH ₃ ) m/z: 193 (M+H) ⁺ ; ¹ HNMR (D ₂ O, 300MHz) δ1.23(t, J=7.8Hz, 3H), 3.84-3.90(m, 3H), 4.37(dd, J=3.4, 11.2Hz, 2H), 4.54(dd, J=7.5, 11.2Hz, ^1H ), 4.64-4.60(m, 2H), 4.92(m, ^1H ), 7.62(s, ^1H ), 8.26(s, ^1H ) ; _Anal. Calcd. for _C11H16N2O - _1.8HCl : C, 51.23; H, 6.96; N, 10.86; Found: C, 51.03; H, 6.70;

Example 24

5-Propyl-3-((2S)-azetidinylmethoxy)pyridine hydrochloride

To 5-(N-tert-butoxycarbonyl-(2S)-azetidinylmethoxy)-3-bromopyridine (1.50 g, 4.37 mmol, [1,3-Bis(diphenylphosphono)-propane]nickel(II) (14.0 mg) was added to the solution of Example 12a) above, followed by propylmagnesium chloride (5.50 ml, 2M in ether, Aldrich). The mixture was refluxed for 3 hours, cooled to room temperature, quenched with saturated aqueous ammonium chloride, and the desired product was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed (silica gel; hexane/ethyl acetate, 10:1-1:1) to give 5-propyl-3-(N-tert-butoxycarbonyl)-(2S)-azetidine methoxy)pyridine as an oil (292 mg, 22%): MS (CI/NH ₃ ) m/z 307 (M+H ⁺ ); ¹ H NMR (CDCl ₃ , 300 MHz) δ 0.95 (t, J=8.3Hz, 3H), 1.42(s, 4.5H), 1.46(s, 4.5H), 1.60-1.70(m, 2H), 2.22-2.40(m, 2H), 2.56(t, J=8.3Hz , 2H), 3.70-3.80(m, 2H), 3.90(m, ^1H ), 4.13(m, ^1H ), 4.51(m, ^1H ), 7.04(s, ^1H ), 8.06(s, ¹ H), 8.18 (d, J = 3.3 Hz, ¹ H). TFA (3ml) was added to 5-propyl-3-(N-tert-butoxycarbonyl)-(2S)-azetidinylmethoxy)pyridine (290mg, 0.950mmol) in dichloromethane (3ml ) in a 0°C solution. After stirring for 30 minutes, the reaction mixture was basified with 15% aqueous sodium hydroxide and extracted with dichloromethane (3X). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Purification by chromatography (silica gel; ethyl acetate/methanol, 10:0.5) afforded the free base of the title compound as an oil (103 mg, 53%): MS (CI/NH ₃ ) m/z 207 (M+H ⁺ ) ; ¹ H NMR (CDCl ₃ , 300MHz) δ0.94(t, J=8.3Hz, 3H), 1.58-1.70(m, 2H), 2.30-2.48(m, 2H), 2.55(t, J=8.3Hz , ^2H ), 3.57(m, ^1H ), 3.76(q, J=8.3Hz, 1H), 4.04-4.10(m, 2H), 4.39(m, ^1H ), 7.03(t, J=3.0Hz , ¹ H), 8.04 (s, ¹ H), 8.14 (d, J=3.3 Hz, ¹ H). The free base was dissolved in ether and saturated HCl in ether was carefully added dropwise. The solvent was removed and the resulting solid was recrystallized from methanol/ether to give the title compound as a yellow hygroscopic solid: mp 79-80°C; MS (CI/ _NH3 ) m/z: 207 (M+H) ⁺ . ¹ HNMR (D ₂ O, 300MHz) δ1.01(t, J=3.05Hz, 3H), 1.68-1.80(m, 2H), 2.62-2.78(m, 2H), 2.80(t, J=7.1Hz, 2H), 4.04-4.21(m, 3H), 4.44-4.60(m, 2H), 7.40(s, ^1H ), 8.04(s, ^1H ), 8.14(s, ^1H ). _Anal. Calcd. for _{C12H18N2O.2HCl.H2O} : C, 48.49; H, 7.46 _; N, _9.43 ; Found: C, 48.35; H, 7.23; N, 9.48.

Example 25

2-Chloro-3-methyl-5-(2-(S)-azetidinylmethoxy)pyridine citrate

25a. 2-Chloro-3-methyl-5-(2-(S)-azetidinylmethoxy)pyridine citrate

At 0°C, to triphenylphosphine (0.55g, 2.09mmol) and (S)-(1-tert-butoxycarbonyl-2-azetidinylmethanol (0.39g, 2.09mmol, Example 7c) 2-Chloro-3-methyl-5-hydroxypyridine (0.20 g, 1.39 mmol, step 25b below) was added to a solution in THF (5 ml). The mixture was warmed to room temperature and diethyl azodicarboxylate was added dropwise Ester (0.33ml, 2.09mmol), the mixture was stirred for 16 hours. The solvent was removed in vacuo, the residue was diluted with hexane and sonicated for 30 minutes. The resulting precipitate was isolated by filtration and washed with hexane. The hexane was removed in vacuo and the residue was washed with Chromatography (silica gel, hexane/ethyl acetate, 1:1) gave a product containing triphenylphosphine oxide.

To a solution of the above product in dichloromethane (6ml) was added trifluoroacetic acid (6ml) at 0°C. The mixture was stirred at 0°C for 40 minutes, then allowed to warm to room temperature and stirred for an additional 30 minutes. Then saturated potassium carbonate was added and the mixture was extracted with dichloromethane. The organic layer was then dried over magnesium sulfate and concentrated. Chromatography (silica gel, 1% ammonium hydroxide/10% methanol/ethyl acetate) of the residue afforded 0.12 g (27%) of 2-chloro-3-methyl-5-(2S)-pyrrolidinylmethoxy base) pyridine as pale yellow oil: MS (CI/NH ₃ ) m/z 213 (M+H ⁺ ); ¹ H NMR (CDCl ₃ , 300 MHz) δ2.34 (s, 3H), 2.34-2.55 (m, 2H), 3.64(m, ^1H ), 3.84(q, J=9Hz, ^1H ), 4.03-4.98(m, 2H), 4.45(m, ^1H ), 7.16(d, J=3.0 Hz, ¹ H), 7.93 (d, J=3.0, ¹ H).

The above product was dissolved in ethanol and treated with citric acid (108 mg) in ethanol. Solvent was removed in vacuo. Grind the resulting salt with diethyl ether and dry it under vacuum to obtain a white powder: mp125-127°C; [α] _D ²⁵ -4.2 (c1.0, MeOH); MS (CI/NH ₃ ) m/z 213 (M+H ⁺ ) ; ¹ HNMR (D ₂ O, 300MHz) δ2.27 (d, J=10.5Hz, ¹ H), 2.36 (s, 3H), 2.41-2.91 (m, 8H), 4.0-4.21 (m, 2H), 4.40 (d, J = 5 Hz, ¹ H), 4.93 (m, ¹ H), 7.48 (d, J = 3.1 Hz, ¹ H), 7.97 (d, J = 3.0, ¹ H). Anal. Calcd. for C ₁₀ H ₁₃ N ₂ OCl 1.2C ₆ H ₈ O ₇ H ₂ O: C, 44.79; H, 5.38; N, 6.07; Found: C, 44.85; H, 5.29; N, 5.91 .

25b.2-Chloro-3-methyl-5-hydroxypyridine

2-Chloro-3-methyl-5-nitropyridine (3.2 g, 18.5 mmol; Maybridge Chemical Co.) was dissolved in a mechanically stirred water/HOAc (60 mL, 5:1) solution. Add iron powder over 5 hours, maintain the temperature below 40°C, and stir until the raw material is consumed. The reaction mixture was filtered and the filter cake was washed with ethyl acetate. The aqueous filtrate was extracted with ethyl acetate and the combined organic portions were washed with saturated sodium bicarbonate solution, dried (magnesium sulfate) and concentrated. The residue was chromatographed (silica gel, chloroform/methanol, 98:2) to give 5-amino-2-chloro-3-picoline as an orange oil (2.34 g, 89%): MS (CI/ _NH3 ) m/z 143 (M+H ⁺ ); NMR (DMSO-d ₆ , 300 MHz) δ 2.17 (s, 3H), 5.40 (brs, 2H), 6.90 (d, J=2.2Hz, ¹ H) , 7.54 (d, J = 2.2 Hz, ¹ H).

To a solution of boron trifluoride etherate (5.8ml, 47.5mol) in DME (18ml) was added dropwise 5-amino-2-chloro-3-methylpyridine (4.5 g, 31.7mol) solution. The mixture was stirred for 15 minutes, then a solution of tert-butyl nitrite (4.5ml, 38mmol) in DME (60ml) was added dropwise. The mixture was stirred at 0°C for 1 hour, then pentane (100ml) was added to give a solid. The solid was collected by filtration and dried to obtain the title compound (6.9 g): ¹ H NMR (MeOH-d ₄ , 300 MHz) δ 2.58 (s, 3H), 8.86 (d, J=2.1 Hz, ¹ H), 9.41 (d, J=2.4Hz, ^1H ).

A solution of the above solid (2.49g) in acetic anhydride (20ml) was heated at 70°C for 4 hours. The solvent was evaporated under reduced pressure and water (200ml) was added. The solution was adjusted to pH 9 with potassium carbonate, followed by extraction with ethyl acetate. The organic layer was then washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was chromatographed (silica gel: hexane/ethyl acetate, 50:50) to give 5-acetoxy-2-chloro-3-picoline as an oil (1.45 g, 76%): ¹ H NMR (CDCl ₃ , 300MHz) δ2.32(s, 3H), 2.39(s, 3H), 7.37(dd, J=1.5, 1.5Hz, ^1H ), 8.06(d, J=2.7, ^1H ); MS (CI/NH ₃ ) m/z 186(M+H) ⁺ , 203(M+NH ₄ ) ⁺ .

The acetate obtained above (1.25 g, 6.7 mmol) was hydrolyzed with 2N aqueous potassium hydroxide solution. The solution was adjusted to pH 6.0 with acetic acid, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried (magnesium sulfate), and concentrated. The residue was chromatographed (silica gel, hexane/ethyl acetate, 50:50) to afford the title compound as an oil (1.2 g, 100%): ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.36 (s, 3H ), 7.19(, J=3.0Hz, ¹ H), 7.83(d, J=3.0H, ¹ H); MS(CI/NH ₃ ) 144(M+H) ⁺ , 146(M+3H) ⁺ , 161(M+H+NH4) ⁺ , 163(M+H+NH4) ⁺ .

Example 26

2-Chloro-3-vinyl-5-((2S)-azetidinylmethoxy)pyridine hydrochloride

To 5-bromo-6-chloro-3-(1-tert-butoxycarbonyl-2-(S)-azetidinemethoxy from Example 17 above in toluene (30ml) Tetrakis(triphenylphosphine)palladium(0) (93mg, 0.081mmol) and vinyltributyltin (0.93ml, 3.18mmol) were added to pyridine (1.00g, 2.65mmol). The mixture was heated at 95°C overnight, then the volatiles were removed in vacuo and the residue was chromatographed (silica gel, dichloromethane/methanol 100:2) to give 2-chloro-3-vinyl-5-(1-tert-butoxy ylcarbonyl-(2S)-azetidinemethoxy)pyridine, as an oil (720 mg, 84%): ¹ HNMR (CDCl ₃ , 300 MHz) δ1.42 (s, 9H), 2.33 (m, 2H ), 3.89(t, J=8.5Hz, 2H), 4.14(m, ^1H ), 4.36(m, ^1H ), 4.52(m, ^1H ), 5.50(d, J=10.9Hz, ^1H ) , 5.80(d, J=17Hz, ^1H ), 6.98(dd, J=17.6Hz, J=11.2Hz, ^1H ), 7.44(d, J=2.7Hz, ^1H ), 8.02(d, J= 2.7Hz, ^1H ). MS (CI/ _NH3 ) m/z 325 (M+H) ⁺ ; treatment of the product with TFA in dichloromethane and extractive workup afforded the free base of the title compound. The free amine was converted to the hydrochloride salt by treatment with HCl in ether to give the title compound as a pale yellow hygroscopic solid: mp 121 °C (dec); MS (CI/ _NH3 ) m/z: 225 (M+ H ⁺ ), 242 (M+NH ₄ ⁺ ). _Anal. Calcd. for _C11H13ClN2O - _1.1 HCl: C, 49.90; H, 5.37; N, 10.58; Found: C, 49.84; H, 5.25; N, 10.27.

Example 27

2-Chloro-3-ethyl-5-((2S)-azetidinylmethoxy)pyridine hydrochloride

Under hydrogen (balloon), 5% Pt on carbon and 2-chloro-3-vinyl-5-(1-tert-butoxycarbonyl-(2S)-azetidinemethoxy) A suspension of pyridine (Example 26 above, 440 mg, 1.36 mmol) in methanol (10 mL) was stirred overnight. The mixture was filtered and the filtrate was concentrated to give 2-chloro-3-ethyl-5-(1-tert-butoxycarbonyl-(2S)-azetidinemethoxy)pyridine as a colorless oil (219 mg , 51%): ¹ H NMR (CDCl ₃ , 300MHz) δ1.25(t, J=7.5Hz, 3H), 1.42(s, 9H), 2.32(m, 2H), 2.71(q, J=7.5Hz , 2H), 3.89(t, J=7.8Hz, 2H), 4.12(dd, J=3.0, 9.8Hz, ^1H ), 4.30(m, ^1H ), 4.50(m, ^1H ), 7.16(d , J = 3.1 Hz, ¹ H), 7.94 (d, J = 3.0 Hz, 1 H); MS (CI/NH ₃ ) m/z 327 (M+H) ⁺ . To a solution of the above product (216mg, 0.66mmol) in dichloromethane (2ml) was added trifluoroacetic acid (1.8ml) at 0°C. The solution was allowed to warm to room temperature. It was then adjusted to pH 11 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane. The organic extracts were then dried over magnesium sulfate and concentrated. The residue was chromatographed (silica gel, dichloromethane/methanol, 100:3-100:15) to give the free base of the title compound (60 mg, 40%) as an oil: ¹ H NMR (CDCl ₃ , 300 MHz) δ1.22 ( m, 3H) 2.38(m, 2H), 2.71(q, J=7.5Hz, 2H) 3.57(m, 1H), 3.80(m, 1H), 4.08(m, 2H), 4.38(m, 1H), 7.15 (d, J=2.4Hz, 1H), 7.92 (d, J=3.0Hz, ^1H ); MS (CI/NH ₃ ) m/z 227 (M+H) ⁺ ; the free base was dissolved in Treatment with 1M HCl in ether gave the hydrochloride salt in THF, which was triturated with ether and dried in vacuo to give the title compound as a white solid: mp 102-104°C; [α] _D ²³ -9.68 (c 0.62, MeOH) ; ¹ H NMR (D ₂ O, 300MHz) δ1.24(t, J=7.5Hz, 3H), 2.71(m, 4H), 4.11(m, 2H), 4.42(d, J=4Hz, 2H), 4.95 (m, 1H), 7.51 (d, J=3Hz, 1H), 8.00 (d, J=3Hz 1H). _Anal. Calcd. _{for C11H15N2OCl.1.1} HCl: C, 49.52; H, 6.08; N, 10.50; Found: C, 49.63; H, 5.89; N, 10.20.

Example 28

2-Chloro-3-ethyl-5-((2S)-azetidinylmethoxy)pyridine hydrochloride

2-Chloro-3-bromo-5-(1-tert-butoxycarbonyl-(2S)-azetidinemethoxy)pyridine (1.20 g, 3.18 mmol, From Example 17 above) was mixed with vinyltributyltin (1.98ml, 6.36mmol), tetrakis(triphenylphosphine)palladium(0) (305mg). The reaction mixture was stirred at 100°C for 16 hours. The solvent was removed in vacuo and the resulting residue was chromatographed (silica gel, hexane:ethyl acetate 5:1) to give 2-chloro-3-(3-propenyl)-5-(1-tert-butoxycarbonyl- (S)-azetidinyl-2-methoxy)pyridine as an oil (947 mg, 88%): MS (CI/NH ₃ ) m/z 339 (M+H) ⁺ ; ¹ H NMR ( CDCl ₃ , 300MHz) δ1.40(s, 9H), 2.20-2.40(m, 2H), 3.45(d, J=6.60Hz, 2H), 3.89(t, J=7.72Hz, 2H), 4.11(dd , J=2.94, 9.92Hz, ^1H ), 4.30(m, ^1H ), 4.51(m, ^1H ), 5.10-5.20(m, 2H), 5.93(m, ^1H ), 7.17(d, J = 2.94 Hz, ¹ H), 7.98 (d, J = 3.31 Hz, ¹ H). A suspension of the above product (945 mg, 2.79 mmol) and 5% Pt on carbon (500 mg) in methanol (10 ml) was stirred under hydrogen for 16 hours. The catalyst was removed by filtration and the solvent was removed in vacuo to give the desired product (770 mg, 81%) as an oil: MS (CI/NH ₃ ) m/z 341 (M+H ⁺ ); ¹ H NMR (CDCl ₃ , 300 MHz) δ0.99(t, J=7.5Hz, 3H), 1.42(s, 9H), 1.60-1.74(m, 2H), 2.20-2.40(m, 2H), 2.65(t, J=7.5Hz, 2H) , 3.89(t, J=7.5Hz, 2H), 4.11(dd J=3.1, 9.8Hz, 1H), 4.32(m, 1H), 4.50(m, 1H), 7.14(d, J=2.7Hz, 1H ), 7.95 (d, J=3.1Hz, 1H). The product from above (759mg, 2.22mmol) was dissolved in dichloromethane (4ml) and THF (3ml) was added at 0°C. After stirring for 30 minutes, the reaction mixture was allowed to warm slowly to room temperature. The reaction mixture was basified with 15% aqueous sodium hydroxide and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Chromatography (silica gel, dichloromethane:methanol, 10:0.4-10:1:0.3 dichloromethane/methanol/ammonium hydroxide) of the crude product afforded the free base of the title compound as an oil (193 mg, 50%): MS (CI/NH ₃ ) m/z 241 (M+H ⁺ ); ¹ H NMR (CDCl ₃ , 300MHz) δ0.98 (t, J=7.35Hz, 3H) 1.58-1.70 (m, 2H), 2.60 -2.70(m, 4H), 3.96-4.10(m, 2H), 4.24-4.32(m, 2H), 4.79(m, 1H), 7.16(d, J=3.4Hz, 1H), 7.91(d, J = 2.9Hz, 1H). The free base from above was dissolved in ether and HCl in ether was carefully added dropwise. The solvent was then removed and the product was recrystallized from methanol/ether to give a white hygroscopic solid: mp 148-150°C; [α] _D -8.54 (c2.67, MeOH); MS (CI/ _NH3 ) m/z: 241(M+H) ⁺ ; ¹ H NMR (D ₂ O, 300MHz) δ0.95(t, J=7.1Hz, 3H) 1.60-1.74(m, 2H), 2.71(t, J=8.1Hz, 4H ), 4.04-4.22(m, 2H), 4.41(d, J=4.1Hz, 2H), 4.97(m, 1H), 7.48(d, J=3.1Hz, ^1H ), 8.00(d, J=3.1 Hz, ¹ H); Anal. Calcd. for C ₁₂ H ₁₇ N ₂ OCl 1.6 HCl 0.1 H ₂ O: C, 47.90; H, 6.30; N, 9.31; Found: C, 47.97; H, 5.91; N , 9.14.

Example 29

3-Butyl-2-chloro-5-((2S)-azetidinylmethoxy)pyridine hydrochloride

Pd(OAc) ₂ (67 mg, Aldrich) and tri-o-tolylphosphine (335 mg, Aldrich) were added to 2-chloro-3-bromo-5-(1-tert-butoxycarbonyl) in toluene (10 ml) -(2S)-azetidinemethoxy)-pyridine (1.00 g, 2.70 mmol, from step 17 above). Butene was bubbled through the mixture over 20 minutes. The reaction mixture was stirred at 100° C. in a sealed tube for 16 hours, cooled to room temperature, then the volatile components were removed under reduced pressure. The residue was chromatographed (silica gel, hexane:ethyl acetate 5:1-2:1) to give an oil (715 mg, 76%): MS (CI/NH ₃ ) m/z 353 (M+H ⁺ ); ¹ H NMR (CDCl ₃ , 300MHz) δ1.13(t, J=7.4Hz, 3H), 1.42(s, 9H), 2.20-2.50(m, 4H), 3.89(t, J=7.7Hz, 2H) , 4.09(m, 1H), 4.28(m, 1H), 5.00(m, 1H), 5.54(m, 1H), 7.1(d, J=2.9Hz, 1H), 7.96(d, J=3.0Hz, 1H). A suspension of 2-chloro-3-butenylpyridine from above (420 mg, 1.19 mmol) and 5% Pt in methanol (10 ml) on charcoal (40 mg) was placed under hydrogen (balloon) for 16 hours. The catalyst was removed by filtration and the solvent was removed in vacuo to give the desired product (310 mg, 74%): MS (CI/NH ₃ ) m/z 355 (M+H ⁺ ); ¹ H NMR (CDCl ₃ , 300 MHz) δ 0.96 ( t, J=7.5Hz, 3H), 1.42(s, 9H), 1.56-1.60(m, 4H), 2.22-2.40(m, 2H), 2.67(t, J=7.8Hz, 2H), 3.84-3.94 (m, 2H), 4.12(m, 1H), 4.32(m, 1H), 4.50(m, 1H), 7.14(d, J=7.1Hz, 1H), 7.94(t, J=7.1Hz, 1H) . The product from above (310mg, 0.87mmol) was dissolved in dichloromethane (2ml) at 0°C and TFA (1.2ml) was added. After stirring for 30 minutes, the reaction mixture was basified with 15% aqueous sodium hydroxide and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The crude product was chromatographed (silica gel, dichloromethane/methanol/ammonium hydroxide, 10:0.4:0-10:1:0.3) to give the free base of the title compound as an oil (165 mg, 75%): MS ( CI/NH ₃ ) m/z 255 (M+H ⁺ ); ¹ H NMR (CDCl ₃ , 300MHz) δ0.95 (t, J=7.1Hz, 3H), 1.32-1.44 (m, 2H), 2.54- 2.66(m, 4H), 2.38-2.56(m, 2H), 2.67(t, J=7.8Hz, 2H), 3.67(m, 1H), 3.86(m, 1H), 4.04-4.20(m, 2H) , 4.49 (m, 1H), 7.15 (d, J=3.1Hz, 1H), 7.91 (d, J=2.7Hz, 1H). The free base from above was dissolved in ether and HCl in ether was carefully added dropwise. The solvent was removed and the resulting salt was recrystallized from methanol/ether to give the title compound as a white solid: mp 88-90 °C; [α] _D -8.00 (c 1.92, MeOH); MS (CI/NH ₃ ) m/ z: 255, (M+H) ⁺ ; ¹ HNMR (D ₂ O, 300MHz) δ0.93 (t, J=7.3Hz, 3H) 1.35-1.42 (m, 2H), 1.58-1.68 (m, 2H) , 2.60-2.78(m, 4H), 4.02-4.22(m, 2H), 4.41(d, J=4.1Hz, 2H), 4.97(m, 1H), 7.50(s, 1H), 8.00(d, J = 2.6 Hz, 1H); Anal. Calcd. for C ₁₃ H ₁₉ N ₂ OCl·1.5HCl·0.1H ₂ O: C, 50.17; H, 6.70; N, 9.00; Found: C, 50.27; H, 6.95; N, 8.89.

Example 30

2-Chloro-3-ethynyl-5-((2S)-azetidinylmethoxy)pyridine hydrochloride

2-Chloro-3-bromo-5-(1-tert-butoxycarbonyl-(2S)-azetidinemethoxy)pyridine (1.00 g, 2.65 mmol, from step 17 above) was mixed with Trimethylsilylacetylene (0.45ml, 3.18mmol), tetrakis(triphenylphosphine)palladium(0) (305mg), copper(I) iodide (50mg) and triethylamine (1ml) in toluene (20ml) )mix. The reaction mixture was stirred at 100°C for 16 hours. The solvent was removed and the residue was chromatographed (silica gel, hexane:ethyl acetate 5:1-2:1) to afford the trimethylsilylethynyl-substituted pyridine as an oil (770 mg, 74%): MS ( CI/NH ₃ ) m/z 395 (M+H ⁺ ); ¹ HNMR (CDCl ₃ , 300MHz) δ1.43 (s, 9H), 2.20-2.40 (m, 2H), 3.80-3.92 (m, 2H) , 4.12(m, ^1H ), 4.32(m, ^1H ), 4.49(m, ^1H ), 7.38(d, J=3.1Hz, ^1H ), 8.05(d, J=3.0Hz, ^1H ) . Solid potassium carbonate (293mg, 2.12mmol) was added to a solution of the product from above (760mg, 1.93mmol) in methanol (20ml). The reaction mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and concentrated to give ethynyl-substituted pyridine (610 mg, 98%): MS (CI/NH ₃ ) m/z 323 (M+H ⁺ ); ¹ HNMR (CDCl ₃ , 300 MHz) δ1.42 (s, 9H), 2.20-2.40(m, 2H), 3.46(s, 1H), 3.84-3.92(m, 2H), 4.07(m, 1H), 4.33(m, 1H), 4.52(m, 1H ), 7.41 (d, J=2.9Hz, 1H), 8.08 (d, J=2.9Hz, 1H). The product from above (605mg, 1.88mmol) was dissolved in dichloromethane (2ml) at 0°C and THF (2ml) was added. After stirring for 30 minutes, the reaction mixture was allowed to warm slowly to room temperature. The mixture was then basified with 15% aqueous sodium hydroxide and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated. Chromatography (silica gel, dichloromethane/methanol/ammonium hydroxide, 10:0.4:0-10:1:0.3) of the crude product afforded the free base of the title compound as an oil (265 mg, 64%): MS (CI /NH ₃ ) m/z 223 (M+H ⁺ ); ¹ H NMR (CDCl ₃ , 300MHz) δ2.20-2.40 (m, 2H), 3.45 (m, 1H), 3.74 (m, 1H), 3.98 -4.06 (m, 2H), 4.25 (m, 1H), 7.38 (d, J=2.9Hz, 1H), 8.08 (d, J=3.0Hz, 1H). The free base from above was dissolved in ether (2ml) and HCl in ether was carefully added dropwise. The solvent was removed and the product was recrystallized from methanol/ether to give a brown hygroscopic solid: mp 90 °C (dec); MS (CI/NH ₃ ) m/z: 223 (M+H) ⁺ ; ¹ H NMR (D ₂ O, 300MHz) δ2.71(q, J=8.2Hz, 2H), 4.04-4.22(m, 2H), 4.44(d, J=4.1Hz, 4H), 4.92-5.00(m, 1H), 7.77( d, J = 3.5 Hz, 1H), 8.19 (d, J = 3.1 Hz, 1H); Anal. Calcd. for C ₁₁ H ₁₁ N ₂ OCl·1.1HCl·0.5H ₂ O: C, 48.60; H, 4.63; N, 10.30; Found: C, 48.70; H, 4.81; N, 10.01.

Example 31

5-((2S)-azetidinylmethoxy)-3-bromo-2-fluoropyridine dibenzoate

31a. 5-((2S)-azetidinylmethoxy)-3-bromo-2-fluoropyridine dibenzoate

Triphenylphosphine (1.19 g, 4.4 mmol) was added to a solution of diethyl azodicarboxylate (0.7 ml, 4.4 mmol) in THF (25 ml) at 0°C, and the reaction mixture was stirred for half an hour. Then 1-tert-butoxycarbonyl-(2S)-azetidinemethanol (0.85g, 4.5mmol, Example 7c) and 5-bromo-6-fluoropyridin-3-ol (0.75g , 4.0 mmol; Step 31d). The mixture was allowed to warm slowly to room temperature and stirred overnight. The solvent was removed and the residue was chromatographed (silica gel, hexane/ethyl acetate, 5:1) to provide 5-bromo-6-fluoro-3-(1-tert-butoxycarbonyl-(2S)-nitrogen Heterobutanylmethoxy)pyridine (1.02 g, 72.3%): MS (CI/NH ₃ ) m/z: 362, 379 (M+H) ⁺ , (M+NH4 ⁺ ); ¹ H NMR ( CDCl ₃ , 300MHz) δ7.82(m, 1H), 7.60(dd, J=3.1, 7.1Hz, 1H), 4.51(m, 1H), 4.35(m, 1H); 4.11(dd, J=3.1, 10.2Hz, 1H), 3.88(m, 2H), 2.33(m, 2H), 1.45(s, 9H). TFA (2ml) was added to a solution of the product from above (0.70g, 1.9mmol) in dichloromethane (2ml) at 0°C. After 30 minutes, the volatile components were removed in vacuo and the residue was diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. Dry over magnesium sulfate and concentrate the organic extracts. The residue was chromatographed (silica gel, dichloromethane:methanol:ammonium hydroxide 10:1:0.1) to afford 282 mg (56%) of the free base of the title compound. The base was converted to a salt by treatment with benzoic acid in ether to afford the title compound (207 mg,): MS (CI/NH ₃ ) m/z: 261, 278 (M+H) ⁺ , (M+NH4 ⁺ ); ¹ H NMR (D ₂ O, 300MHz) δ2.69 (dd, J=7.0, 8.5, 2H), 4.11 (m, 1H), 4.40 (d, J=4.4, 2H), 4.63 (m, 1H), 4.95 (m, 1H), 7.53 (m, 8H), 7.93 (m, 7H); Anal. Calcd. for C ₉ H ₁₀ N ₂ OBrF·2C ₆ H ₅ COOH: C, 54.67; H, 4.39; N, 5.54; Found: C, 54.45; H, 4.25; N, 5.58.

31b. 3-Bromo-2-(4-nitrophenylazo)-5-hydroxypyridine

5-Bromo-5-pyridinol (8.7 g, 0.050 mmol) and potassium hydroxide (1.1 g, 19.6 mmol) from Example 12b were dissolved in water (200 ml). A suspension of p-nitrobenzenetetrafluoroborate diazonium salt (11.8 g, 0.50 mol) prepared as described in J. Org. Chem., 44:1572-15783 (1979) was added. The reaction was stirred for 1 hour, diluted with acetic acid (50ml) and filtered. The crude product was air-dried and then chromatographed (silica gel, chloroform/methanol, 95:5-90:10) to provide the title compound (5.45 g, yield 34%): MS (CI/NH ₃ ) m/z: 323, 325(M+H) ⁺ ; NMR(DMSO-d ₆ , 300MHz) δ8.48-8.43(m, 2H), 8.21(d, J=2.4Hz, 1H), 8.09-8.06(m, 2H), 7.72 (d, J=2.4Hz, 1H).

31c. 2-Amino-3-bromo-5-hydroxypyridine

The compound from 31b above (5.0 g, 15.8 mmol) and tin chloride (25 g, 111 mmol) were suspended in concentrated hydrochloric acid and ethanol (150 ml), and the mixture was heated at reflux for 1 hour. The mixture was cooled to 0 °C, then filtered. The filtrate was neutralized with sodium bicarbonate (180 g) and extracted with ethyl acetate. The organic extracts were washed with brine, dried (magnesium sulfate) and concentrated. The residue was chromatographed (silica gel, chloroform/methanol/ammonium hydroxide, 95:5:0.5-90:10:1) to provide the title compound (3.3 g, 34% yield): MS (CI/NH ₃ ) m/ z: 189, 191 (M+H) ⁺ ; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.57 (d, J=2.6 Hz, 1H), 7.43 (d, J=2.6 Hz, 1H).

31d.3-Bromo-2-fluoro-5-hydroxypyridine

The compound obtained from 31c (3.0g, 15.9mmol) was dissolved in HF·pyridine (50ml), the solution was cooled to 0°C and stirred under nitrogen, and sodium nitrite (1.09g, 15.8 mmol). The mixture was heated to 50°C for 1 hour, cooled to 0°C, and basified with 20% aqueous sodium hydroxide. The aqueous phase was washed with dichloromethane (5 x 100ml), neutralized with hydrochloric acid and extracted with ethyl acetate (5 x 100ml). The organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. The title compound was obtained as a brown solid: MS (CI/NH ₃ ) m/z: 192, 194 (M+H) ⁺ ; 1H NMR (DMSO-d ₆ , 300 MHz) δ 9.38 (d, J = 2.6 Hz, 1H), 9.20 (d, J = 2.6 Hz, 1H).

Example 32

5-((2S)-azetidinylmethoxy)-3-methyl-2-fluoropyridine benzoate

32a. 5-((2S)-azetidinylmethoxy)-3-methyl-2-fluoropyridine benzoate

According to the method of Example 6, with 2-fluoro-5-hydroxy-3-picoline (below Example 32e) and (S)-1-benzyloxycarbonyl-2-azetidinemethanol (above Example 7c) replace 3-hydroxypyridine and (R)-1-benzyloxycarbonyl-2-azetidinemethanol to obtain 6-fluoro-5-methyl-3-(1-benzyloxy Carbonyl-(2S)-azetidinylmethoxy)pyridine (60% yield): MS(CI/NH ₃ ) m/z: 331(M+H) ⁺ , 348(M+NH ₄ ⁺ ); ¹ H NMR (CDCl ₃ , 300MHz) δ7.63 (br s, 1H), 7.29 (m, 5H), 7.18 (br s, 1H), 5.05 (m, 2H), 4.59 (m, 1H); 4.3 (br s, 1H), 4.09 (m, 1H), 3.99 (m, 1H), 2.26-2.05 (m, 2H), 2.05 (s, 3H). The benzyloxycarbonyl group of the above product was removed by hydrogenolysis (10% Pd/C, methanol, one atmosphere of hydrogen) and the salt was prepared by treating the free amine with benzoic acid in diethyl ether to afford the title compound as an off-white solid ( 53%): mp 104-108°C; [α] _D -5.55 (c0.55, MeOH); ¹ H NMR (DMSO) δ7.90 (m, 2H), 7.70 (s, 1H), 7.51-7.48 ( m, 2H), 7.42-7.39(t, J=7.2, 2H), 4.27(m, 1H), 4.17(dd, J=7.3, 10.4Hz, 2H), 4.08(dd, J=4.9, 10.4Hz, 1H), 3.79(m, 1H), 3.47(m, 1H), 2.35(m, 1H), 2.19(s, 3H), 2.16(m, 1H); MS(CI/NH ₃ ) m/z: 197 (M+H), 214(M+NH ₄ ) ⁺ ; Anal. Calcd. for C ₁₀ H ₁₃ N ₂ OF·C ₇ H ₆ O ₂ : C, 64.14; H, 6.02; N, 8.80; Found: C , 63.90; H, 6.10; N, 8.70.

32b. 2-Fluoro-3-methyl-5-nitropyridine

2-Chloro-3-methyl-5-nitropyridine (15.0 g, 86.9 mmol; obtained from Maybridge Chemical Co.), KF (12 g, 258 mmol) and tetraphenylphosphonium bromide (20 g, 47.7 mmol) were mixed in Mix in 200 mL of acetonitrile and heat at reflux for 4 days. The mixture was diluted with ether (500ml), filtered and the solution was concentrated. The residue was triturated with hot hexane, then the combined hexane solution was concentrated to give 8.4 g (60%) of the title compound: ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.95 (dd, J=1.6 Hz, 1H), 8.43 (m, 1H), 2.42 (s, 1H); MS (CI/NH ₃ ) m/z: 157 (M+H) ⁺ .

32c.3-Amino-6-fluoro-5-methylpyridine

2-Fluoro-3-methyl-5-nitropyridine (from step 32b) was mixed with 100 mg 5% Pd/C in ethanol (100 ml) and the mixture was stirred under hydrogen for 16 hours. The mixture was filtered and concentrated. The crude product was chromatographed (silica gel, chloroform/methanol, 99:1:-94:6) to obtain 5.2 g (78%) of the title compound: ¹ H NMR (DMSO-d ₆ , 300 MHz) δ7.26 (t, J= 2.7Hz, 1H), 6.95(dd, J=8.1Hz, 1H), 5.11(br, s, 2H), 2.10(s, 3H); MS(CI/NH ₃ ) m/z: 127(M+H ) ⁺ ; 144(M+NH ₄ ) ⁺ .

32d.3-Acetoxy-6-fluoro-5-methylpyridine

The product from Step 32c (5.1 g, 40 mmol) dissolved in DME (30 ml) was added to boron trifluoride etherate (10 ml, 81 mmol) at -15°C under nitrogen. Tert-butyl nitrite (5.5 ml, 46 mmol, Aldrich) was added at a rate to maintain the temperature below 0°C. Additional DME (25ml) was added. After standing at -10°C for 10 minutes, the reaction was warmed to 5°C and stirred for 30 minutes. Pentane (400ml) was added to the reaction mixture and the resulting solid was collected by suction filtration, washed with cold diethyl ether, air dried and dissolved in 100ml of acetic anhydride. The solution was heated to 70±5°C for 1 hour. The solvent was removed in vacuo, the residue was suspended in saturated aqueous sodium carbonate (200ml) and extracted with ether. The ether solution was dried (magnesium sulfate) and concentrated. The crude product was chromatographed (silica gel, hexane/ethyl acetate, 9:1-7:3) to give the title compound (3.62 g, 53%): MS m/z: 170 (M+H) ⁺ , 187 (M +NH ₄ ) ⁺ ; ¹ H NMR (CDCl ₃ , 300MHz) δ7.8(m, 1H), 7.34(m, 1H), 2.32(s, 3H), 2.29(s, 3H);

32e.2-Fluoro-5-hydroxy-3-methylpyridine

The product from step 32d (3.6g, 21.3mmol) was dissolved in 20% aqueous sodium hydroxide (25ml). After the starting material was consumed, hydrochloric acid was added to neutralize the solution. The aqueous mixture was extracted with ethyl acetate. The organic extracts were dried (magnesium sulfate) and the solvent was evaporated. The crude product was triturated with hexane to give 2.35 g (87%) of the title compound: MS (CI/NH ₃ ) m/z: 128 (M+H) ⁺ , 145 (M+NH ₄ ) ⁺ ; ¹ H NMR (CDCl ₃ , 300MHz) δ7.61 (t, J=2.2, 1H), 7.17 (m, 1H), 2.25 (s, 3H).

Example 33

5-((2S)-azetidinylmethoxy)-3-chloro-2-fluoropyridine p-toluenesulfonate

33a. 5-((2S)-azetidinylmethoxy)-3-chloro-2-fluoropyridine p-toluenesulfonate

According to the method of Example 10, 3-chloro-fluoro-5-hydroxypyridine (3.0ml) was used instead of 3-fluoro-5-hydroxypyridine to prepare 5-(1-tert-butoxycarbonyl-(2S) -azetidinylmethoxy)-3-chloro-2-fluoropyridine (668 mg, 70%) as a colorless oil: [α] _D -56.5 (c2.7, dichloromethane) ; ¹ H NMR (CDCl ₃ ) δ1.43 (s, 9H), 2.24-2.40 (m, 2H), 3.84-3.91 (m, 2H), 4.12 (dd, J=2.7, 11.2Hz, 1H), 4.36 (m, 1H), 4.50(m, 1H); 7.46(dd, J=3.1, 7.5Hz, 1H), 7.78(dd, J=2.0, 2.7Hz, 1H); MS(CI/NH ₃ )m/ z: 317, 319 (M+H) ⁺ . A solution of the above compound (780 mg, 2.46 mmol) in 1:1 dichloromethane/TFA was stirred at 0°C. After 30 minutes the reaction solution was concentrated and the residue was diluted with dichloromethane and washed with saturated potassium carbonate. The organic extracts were dried (sodium sulfate) and concentrated. Chromatography (silica gel, 90:10:1-90:10:1 dichloromethane/methanol/ammonium hydroxide) provided 407 mg (76%) of the free base of the title compound: MS (CI/ _NH3 ) m/z: 217 , 219(M+H) ⁺ . The free amine (387mg, 1.79mmol) was dissolved in methanol (5ml) and p-toluenesulfonic acid monohydrate (340mg, 1.79mmol) was added. The solution was concentrated, and the solid was recrystallized from methanol/hexane to give the title compound as a white solid: mp 99°C; ¹ H NMR (D ₂ O) δ 2.40 (s, 3H), 2.69 (q, J=8.5Hz, 2H ), 4.05-4.18(m, 2H), 4.41(d, J=4.3Hz, 2H), 4.94(m, 1H), 7.37(d, J=8.0Hz, 2H), 7.69(d, J=8.0Hz , 2H), 7.82 (dd, J=3.1, 7.31Hz, 1H), 7.87 (m, 1H); MS (CI/NH ₃ ) m/z: 217, 219 (M+H) ⁺ , 234, 236 ( M+NH ₄ ) ⁺ ; Anal. Calcd. for C ₉ H ₁₀ N ₂ OFCl·C ₇ H ₈ O ₃ : C, 49.42; H, 4.67; N, 7.20; Found: C, 49.14; H, 4.56; N , 6.98.

33b. 2-Chloro-2-(4-nitrophenylazo)-5-hydroxypyridine

At 0°C, to a solution of 5-chloro-3-pyridinol (20.0g, 0.154mmol, Aldrich) and potassium hydroxide (13.0g, 0.232mmol) in water (300ml) was added p-nitrobenzenetetrafluoroboric acid Nitrogen salt (36.6 g, 0.154 mmol, Aldrich). After 1 hour, 50 ml of glacial acetic acid was added, and the bright red precipitate was filtered and air-dried. Chromatography (silica gel, dichloromethane/methanol, 95:5-90:10) provided the title compound as a bright red solid (28.8 g, 67%): ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.14 ( d, J=2.4Hz, 1H), 7.89(d, J=2.4Hz, 1H), 8.00(m, 2H), 8.39(m, 2H); MS(CI/NH ₃ ) m/z: 279, 281 (M+H) ⁺ ;

33c. 2-Amino-3-chloro-5-hydroxypyridine

At 0°C, potassium borohydride (12.0 g, 221 mmol, nitrogen generation) was added in portions to the diazo compound (8.82 g, 31.7 mmol) and copper(I) chloride (9.40 g, 95.0 mmol, Aldrich) in step 33b suspension in methanol (150ml). The dark mixture was allowed to warm to room temperature, stirred for 1 hour, then filtered and concentrated. The residue was dissolved in glacial acetic acid (75ml) and 30% hydrobromic acid/HOAC (75ml) was added. The mixture was filtered (HOAc wash) and the filtrate was concentrated to afford 8.64 g (89%) of the unpurified title compound as the dihydrobromide salt: ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 5.40 (br s, 1H) , 7.16 (d, J=2.6Hz, 1H), 7.56 (d, J=2.2Hz, 1H), 8.25 (br s, 2H); MS (CI/NH ₃ ) m/z: 145, 147 (M+ H) ⁺ .

33d.3-Chloro-2-fluoro-5-hydroxypyridine

To a 0° C. solution of the compound from 33c (11.8 g, 38.4 mmol) dissolved in HF·pyridine (100 g, Aldrich) was added sodium nitrite (2.92 g, 42.3 mmol) in portions. The reaction mixture was heated to 50°C for 1 hour, then cooled to 0°C and basified with 20% aqueous sodium hydroxide. The aqueous phase was washed with EtOAc, neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The latter extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatographic purification (silica gel, hexane/ethyl acetate, 50:50) provided 1.49 g (25%) of the title compound as a brown solid: ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.54 (m, 1H), 7.67 (m, 1H), 10.44 (s, 1H); MS (CI/NH ₃ ) m/z: 148, 150 (M+H) ⁺ ;

Example 34

5-Bromo-6-methyl-3-[(2S)-azetidinylmethoxy)pyridine dihydrochloride

34a. 5-Bromo-6-methyl-3-((2S)-azetidinylmethoxy)pyridine dihydrochloride

Triphenylphosphine (6.3g, 24mmol) was dissolved in THF (100ml), cooled to 0°C and treated with DEAD (3.8ml, 24mmol) for 15 minutes. 5-Bromo-6-methyl-3-pyridinol (3 g, 16 mmol, see Example 34e below) and 1-tert-butoxycarbonyl-(2S)-azetidinemethanol (3.4 g, 18 mmol, from step 7c), the mixture was allowed to warm slowly to room temperature. After 3 days, the solvent was evaporated and the residue was chromatographed (silica gel, hexane/ethyl acetate, 4:1) to afford the title compound as an oil contaminated with hydrazine by-product derived from DEAD: MS (CI/ _NH3 )m /z: 357(M+H) ⁺ , 279. The product from above (0.40g, 1.12mmol) was dissolved in dichloromethane (4ml) and treated with TFA (2ml) at 0°C for 1 hour. The solution was concentrated, and the residue was diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic extracts were washed with water and dried (magnesium sulfate). Evaporation of the solvent afforded 0.25 g (76%) of the neutral product, which was dissolved in ether and treated with 1N HCl in ether. The resulting solid was collected and washed with fresh ether to provide 151 mg (41%) of the title compound: mp 153-155°C; [α] _D -7.4 (c 0.54, MeOH); ¹ H NMR (CD ₃ OD) δ 2.63 -2.76(m, 2H), 2.78(s, 3H), 4.04-4.18(m, 2H), 4.50-4.63(m, 2H), 4.88-4.96(m, 1H), 8.50(d, J=2Hz, 1H), 8.10 (d, J=2Hz, 1H); MS (CI/NH ₃ ) m/z: 257 (M+H) ⁺ , 274 (M+NH ₄ ) ⁺ ; C ₁₀ H ₁₃ N ₂ OBr· Anal. Calcd. for 2HCl: C, 36.39; H, 4.58; N, 8.49; Found: C, 36.31; H, 4.66; N, 8.41.

34b. 3-Bromo-2-methyl-5-nitropyridine

A solution of diethyl malonate (17.6 mL, 0.116 mol) in diethyl ether (250 mL) was treated with sodium hydride (80% in mineral oil, 3.5 g, 0.116 mol) at room temperature and the reaction mixture was stirred for 1 hour. Then 3-bromo-2-chloro-5-nitropyridine (25 g, 105 mmol) was added in portions over 5 minutes (according to the method of V.Koch and S.Schnatterer, Synthesis, 1990, 499-501 from 2-hydroxy -5-nitropyridine preparation). After stirring the mixture for 1 hour, the solvent was evaporated and the residue was heated at 100°C for 1 hour. After the mixture was cooled, 12N sulfuric acid was added and the mixture was heated at reflux for 16 hours. The mixture was allowed to cool to room temperature, then cooled further while treating with 50% sodium hydroxide to create a basic pH. The resulting solution was extracted with chloroform (3X), the organic extract was washed with water, dried (magnesium sulfate) and evaporated to give 17.1 g of the title compound as a red oil: ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.81 (s, 3H) , 8.61 (d, J=2Hz, 1H), 9.26 (d, J=2Hz, 1H).

34c.5-Amino-3-bromo-2-methylpyridine

The compound of Example 34b above (17.1 g, 78.8 mmol) was dissolved in HOAc (50 mL) and water (150 mL), treated with the addition of iron powder (13.3 g, 236 mmol) in portions over 2 hours, the mixture was filtered and washed with ethyl acetate Ester washes the filter cake. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic portions were washed with 1M sodium bicarbonate and water, then dried (magnesium sulfate) and concentrated to give 12.65 g (65%) of the title compound: MS (CI/NH ₃ ) m/z 187 (M+H ⁺ ), 204 (M+NH ₄ ) ⁺ .

34d.5-Acetoxy-3-bromo-2-methylpyridine

Following the procedure of Example If, the compound of Example 34c (12.6 g, 67 mmol) was treated with tert-butyl nitrite and _BF3 - _OEt2 , followed by acetic anhydride. The crude product was chromatographed (silica gel, hexane/ethyl acetate, 4:1) to give the title compound (12.0 g, 58%): MS (CI/NH ₃ ) m/z: 230 (M+H) ⁺ .

34e.3-Bromo-5-hydroxy-2-methylpyridine

The product from Example 34d was stirred with 15% aqueous sodium hydroxide (75 mL) at 0°C and the mixture was allowed to warm to room temperature. After 1 hour, the mixture was acidified with 6N aqueous hydrochloric acid under cooling, and the resulting suspension was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (magnesium sulfate) and concentrated to afford 7.0 g (95%) of the title compound, ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.59 (s, 3H), 7.46 (d, J = 2 Hz, 1H), 8.10 (d, J=2Hz, 1H). MS (CI/NH ₃ ) m/z: 188 (M+H) ⁺ , 207 (M+NH ₄ ) ⁺ .

Example 35

6-Methyl-5-vinyl-3-((2S)-azetidinylmethoxy)pyridine hydrochloride

5-Bromo-6-methyl was treated with vinyltributyltin (1.62ml, 5.56mmol) and tetrakis(triphenylphosphine)palladium(0) (0.29g, 0.25mmol) in toluene (30ml) at 90°C Ethyl-3-(1-tert-butoxycarbonyl-(2S)-azetidinylmethoxy)pyridine (0.95 g, 2.7 mmol, Step 34a above) overnight. The reaction was cooled to room temperature and chromatographed on silica gel with 2:1 hexane-ethyl acetate to give 6-methyl-5-vinyl-3-(1-tert-butoxycarbonyl-(2S)- Azetidinylmethoxy)pyridine (0.49 g, 60%): MS (CI/NH ₃ ) m/z: 305 (M+H ⁺ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ1.42 (s, 9H), 2.22-2.38 (m, 2H), 2.52 (s, 3H), 3.91 (t, J=2, 6Hz, 1H), 4.13 (dd, J=3, 10Hz, 1H), 4.30- 4.36(m, 1H), 4.49-4.55(m, 1H), 5.40(dd, J=1, 11Hz, 1H), 5.64(dd, J=1, 17Hz, 1H), 6.84(dd, J=11, 17Hz, 1H), 7.32(d, J=3Hz, 1H), 8.13(d, J=3Hz, 1H). The above product (0.47 g, 1.53 mmol) was treated with 8 mL of 1:1 TFA-dichloromethane at 0°C for 2 hours. The volatiles were removed in vacuo and the residue was diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic layers were washed with water and dried over magnesium sulfate to provide the product (277 mg, 89% yield). Half of the sample was dissolved in ether and treated with 1M HCl in ether to afford 85 mg of the title compound as an off-white solid: mp 154-155°C; [α] _D -8.9 (c 0.45, MeOH); ¹ H NMR (CD ₃ OD) δ2 .63-2.77(m, 2H), 2.74(s, 3H), 4.08-4.16(m, 2H), 4.52-4.64(m, 2H), 4.85-4.95(m, 1H), 5.80(d, J= 11Hz, 1H), 6.15(d, J=17Hz, 1H); 7.02(dd, J=11, 17Hz, 1H), 8.36(d, J=2Hz, 1H), 8.48(d, J=2Hz, 1H) ; MS (CI/NH ₃ ) m/z: 205 (M+H) ⁺ ; Anal. Calcd. for C ₁₂ H ₁₆ N ₂ O·2.1 HCl: C, 51.32; H, 6.50; N, 9.97; Found: C, 51.60; H, 6.21; N, 9.82.

Example 36

6-Ethyl-6-methyl-3-((2S)-azetidinylmethoxy)pyridine hydrochloride

6-Methyl-5-vinyl-3-(1-tert-butoxycarbonyl-(2S)-azetidinylmethoxy)pyridine (0.26 g, 0.86 mmol, obtained from Example 35 above ) was dissolved in methanol (15ml) and treated with 10% Pd/C (50mg) and one atmosphere of hydrogen. After 1 day, the catalyst was removed, the solvent was evaporated, and the residue was chromatographed (silica gel, hexane-ethyl acetate, 1:1) to give 5-ethyl-6-methyl-3-(1-tert-butoxycarbonyl- 2-(S)-azetidinylmethoxy)pyridine (0.12 g, 45%). MS (CI/NH ₃ ) m/z: 307 (M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ) δ1.23 (t, J=7Hz, 3H), 1.42 (s, 9H), 2.23- 2.38(m, 2H), 2.47(s, 3H), 2.60(q, J=7Hz, 2H), 3.86-3.93(m, 2H), 4.12(dd, J=3, 9Hz, 1H), 4.29(dd , J=5.10Hz, 1H), 4.43-4.53(m, 1H), 7.04(d, J=3Hz, 1H), 8.05(d, J=3Hz, 1H). The above product (0.26 g, 0.85 mmol) was treated with 10 mL of 1:1 TFA-dichloromethane at 0°C for 1 hour. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and evaporated to provide the free base of the title compound (132 mg, 75%). This was dissolved in ether and treated with 1M HCl in ether and the resulting salt collected by filtration to afford the title compound (52 mg, 25%). Evaporation of the mother liquor further afforded 73 mg of the title compound: mp 150-153°C; [α] _D -7.6 (c0.62, MeOH); ¹ H NMR (300 MHz, CD ₃ OD) δ 1.34 (t, J=7Hz, 3H), 2.63-2.76(m, 2H), 2.72(s, 3H), 4.04-4.19(m, 2H), 4.49-4.63(m, 2H), 4.88-4.97(m, ^1H ), 8.14(d, J= 2Hz, 1H); 8.40 (d, J = 2Hz, 1H); MS (CI/NH ₃ ) m/z: 207 (M+H) ⁺ ; C ₁₂ H ₁₈ N ₂ O·2HCl·0.1H ₂ O Anal. Calcd.: C, 51.29; H, 7.25; N, 9.97; Found: C, 51.21; H, 7.14; N, 9.77.

Examples 37-53

The R-enantiomers of formula (I) having X and Y as defined in Table 5 can each be prepared according to the method for the corresponding (S)-enantiomer in Table 5, using the corresponding N-protected (R)- 2-Azetidinemethanol was used as starting material instead of N-protected (S)-2-azetidinemethanol. Ex. x Y Adopt the method of embodiment: 37 Me h 20 38 h Cl twenty one 39 h Br 12 40 h Et twenty three 41 h n-Pr twenty four 42 h vinyl twenty two 43 Cl Me 25 44 Cl Et 27 45 Cl n-Pr 28 46 Cl n-Bu 29 47 Cl vinyl 26 48 Cl Ethynyl 30 49 f Br 31 50 f Me 32 51 Me Br 34 52 Me Et 35 53 Me vinyl 35

Example 54

1-(N-BOC-L-alanyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

To a solution of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine (from Example 8, 102 mg, 0.60 mmol) in THF (20 ml) was added N-BOC-L-alanine acid (106mg, 1.0eq), 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107mg, 1.0eq) and 4-(dimethylamino)pyridine (68mg, 1.0 eq), and the resulting mixture was stirred at 20-25°C for about 2 hours. The volatiles were removed in vacuo and the residue was purified by chromatography eluting with 10% methanol/dichloromethane. The product was obtained as a yellow oil (155 mg, 73%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.85 (m, 1H), 7.37 (ddd, J = 3, 7, 10 Hz, 1 H), 6.84 (dd, J =3, 9Hz, 1H), 5.0-52(m, 1H), 4.0-4.7(br m, 5H), 3.49(d, J=6Hz, 1H), 2.47(m, 2H), 1.41(s, 9H ), 1.29 (d, J=7Hz, 3H): MS (CI/NH ₃ ) m/e: 354, 298, 254; [α] _D ²⁰ -49.78° (c=0.10, dichloromethane); C _{17 Anal .} Calcd. for _H24N3O4F · _0.55H2O : C, 56.20; H, 6.96; N, 11.57; Found: C, 56.23; H, 7.03; N, 11.26.

Example 55

1-(N-acetyl-L-phenylalanyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared as in Example 54, substituting N-acetyl-L-phenylalanine for N-BOC-L-alanine. The product was obtained as a colorless oil with a yield of 56%: ¹ H NMR (300 MHz, CDCl ₃ ) δ7.81 (m, 1H), 7.1-7.4 (m, 6H), 6.84 (m, 1H), 6.12 (m, 1H), 4.4-5.0(m, 2H), 3.5-4.2(m, 3H), 2.97(m, 3H); 2.0-2.2(m, 2H), 1.96(s, 3H); MS(CI/NH ₃ ) m/e: 372; [α] _D ²⁰ -46.21° (c=0.20, dichloromethane); Anal. Calcd. for C ₂₀ H ₂₂ N ₃ O ₃ F: C, 64.68; H, 5.97; N, 11.31 ; Found: C, 64.44; H, 5.99; N, 11.06.

Example 56

1-(N-acetyl-L-alanyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared as in Example 54, substituting N-acetyl-L-alanine for N-BOC-L-alanine. The product was obtained as a colorless oil with a yield of 78%: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.85 (m, 1H), 7.37 (m, 1H), 6.86m(1), 6.2 (m, 1H), 4.4-4.8(m, 3H), 3.9-4.4(m, 3H); 2.48(m, 2H), 1.96(s, 3H), 1.30(d, J=7Hz, 3H); MS(CI/NH ₃ ) m/e 296, 183; [α _{] D} ²⁰ -86.72° (c0.15, dichloromethane); Anal _. Calcd. for C14H18N3O3F _0.4H2O : C _{, 56.58} ; H, 6.26; N, 13.89; Found: C, 55.66; H, 6.38; N, 13.93.

Example 57

1-(N-BOC-L-phenylalanyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared as in Example 54, substituting N-BOC-L-phenylalanine for N-BOC-L-alanine. The product was obtained as a light oily product with a yield of 98%: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.83 (m, 1H), 7.30 (m, 5H), 7.1 5 (m, 1H), 6.83 (dd, J= 3, 5Hz, 1H), 5.18(m, 1H), 4.46(m, 2H), 4.25(m, 1H), 3.6-4.2(m, 2H), 2.96(m, 3H); 2.13(m, 2H) , 1.41 (s, 9H); MS (CL/NH ₃ ) m/e: 430, 330; [α] _D ²⁰ 36.72° (c=0.15, dichloromethane); C ₂₃ H ₂₈ N ₃ O ₄ F· _Anal . Calcd. for 0.1 H2O: C, 64.05; H, 6.59; N, 9.74; Found: C, 64.03; H, 6.28; N, 9.73.

Example 58

1-(Monomethylphthaloyl) Prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared as in Example 54, substituting monomethylphthalate for N-BOC-L-alanine. The product was obtained as a colorless oil with a yield of 99%: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (m, 2H), 7.52 (m, 3H), 7.22 (m, 1H), 6.87 (m, 1H) , 4.1-4.9 (m, 3H), 3.91 (m, 3H); 3.78 (m, 2H), 2.44 (s, 2H); MS (DCI/NH ₃ ) m/e 345; [α] _D ²⁰ -18.21 °(c=0.20, dichloromethane); _Anal . Calcd. for _C18H17N3O4F ·0.55H2O: C, _61.03 ; H, _5.15 ; N, 7.91; Found: C _, 61.09; H , 5.12; N, 7.90.

Example 59

1-(N-acetyl-D-phenylalanyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared as in Example 54, substituting N-acetyl-D-phenylalanine for N-BOC-L-alanine. The product was obtained as a white foam in 97% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.82 (m, 1H), 7.2-7.5 (m, 6H), 6.87 (m, 1H), 6.27 (m , 1H), 4.6-5.0(m, 2H), 3.8-4.2(m, 3H), 3.54(m, 1H); 2.9-3.1(m, 2H), 2.01(s, 3H); 1.8-2.4(m , 2H); MS (DCI/NH ₃ ) m/e: 372; [α] _D ²⁰ +56.67° (c=0.15, dichloromethane); C ₂₀ H ₂₂ N ₃ O ₃ F·0.45H ₂ O Anal. Calcd.: C, 63.30; H, 6.08; N, 11.07; Found: C, 63.29; H, 5.93; N, 11.09.

Example 60

1-(N-acetyl-D-alanyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared as in Example 54, substituting N-acetyl-D-alanine for N-BOC-L-alanine. The product was obtained as a pale yellow oil with a yield of 86%: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.86 (m, 1H), 7.36 (m, 1H), 6.85 (m, 1H), 6.26 (m, 1H) , 4.71(m, 1H), 4.1-4.6(m, 5H); 2.47(m, 2H), 1.98(s, 3H), 1.22(d, J=7Hz, 3H); MS(DCI/NH ₃ )m /e 296; [α] _D ²⁰ +95.67° (c=0.30, dichloromethane); Anal. Calcd. for C ₁₄ H ₁₈ N ₃ O ₃ F 0.40 H ₂ O: C, 55.58; H, 6.26; N , 13.89; Found: C, 55.57; H, 6.30; N, 13.80.

Example 61

1-(4-(Diethylaminomethyl)benzoyl) Prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared as in Example 54, substituting 4-(dimethylaminomethyl)benzoic acid for its N-BOC-L-alanine. The product was obtained as a pale yellow oil with a yield of 59%: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.90 (m, 1H), 7.54 (m, 2H), 7.38 (m, 4H), 6.83 (m, 1H) , 4.88(m, 1H), 4.1-4.6(m, 3H); 3.60(br s, 2H), 2.50(m, 6H), 1.03(d, J=7Hz, 6H); MS(DCI/NH ₃ ) m/e 372; [α] _D ²⁰ +97.00° (c=0.60, dichloromethane); Anal. Calcd. for C ₂₁ H ₂₆ N ₃ O ₂ F·0.3 H ₂ O: C, 66.93; H, 7.11; N, 11.15; Found: C, 66.99; H, 7.13; N, 11.17.

Example 62

1-9(N-BOC-D-phenylalanyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared as in Example 54, substituting N-BOC-D-phenylalanine for N-BOC-L-alanine. The product was obtained as a colorless oil with a yield of 79%: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.82 (m, 1H), 7.31 (m3), 7.19 (m, 3H), 6.87 (m, 1H), 5.52 (m, 1H), 4.62(m, 1H), 3.7-4.4(m, 4H); 3.53(m, 1H); 2.95(m, 2H), 1.8-2.4(m, 2H); 1.37&1.44( s, 9H); MS (DCI/NH ₃ ) m/e: 430, 274, 330; [α] _D ²⁰ +33.20° (c=0.20, dichloromethane); C ₂₃ H ₂₈ N ₃ O ₄ F· _Anal . Calcd. for 0.65H2O: C, 62.61; H, 6.69; N, 9.52; Found: C, 62.64; H, 6.66; N, 9.36.

Example 63

1-(N-BOC-D-alanyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared as in Example 54, substituting N-BOC-D-alanine for N-BOC-L-alanine. The product was obtained as a colorless oil with a yield of 99%: ¹ H NMR (300MHz, CDCl ₃ ) δ7.87 (m, 1H), 7.36 (ddd, J=3, 6, 9Hz, 1H), 6.85 (dd, J =3, 9Hz, 1H), 5.20(m, 1H), 4.72(m, 1H), 4.53(m, 1H); 4.1-4.3(m, 4H); 2.46(m, 2H), 1.43(s, 9H ); 1.20 (d, J=7Hz, 3H); MS (DCI/NH ₃ ) m/e: 354,298,254; [α] _D ²⁰ +79.20° (c=0.52, dichloromethane); C _{17 Anal.} Calcd. for _H24N3O4F · _0.25H2O : C, 57.05; H, 6.90; N _, 11.74; Found: C, 57.09; H, 6.91; N, 11.58.

Example 64

1-(2-oxo-tetrahydrofuran-4-(S)-carboyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared as in Example 54, substituting S-4-carboxybutyrolactone for N-BOC-L-alanine. The product was obtained as a colorless oil with a yield of 65%: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.86 (m, 1H), 7.37 (m, 1H), 6.86 (m, 1H), 4.7-5.1 (m, 2H), 4.0-4.6 (m, 4H); 2.43 (m, 6); MS (CI/NH ₃ ) m/e 295, 199, 174, 123; [α] _D ²⁰ +94.0° (c=0.30, Dichloromethane); _Anal. Calcd. for _C14H15N2O4F · _0.4H2O : C, _55.77 ; H, 5.28; N, _9.24 ; Found: C, 55.88; H, 5.39; N, 9.28 .

Example 65

1-(2-oxo-tetrahydrofuran-4-(R)-formyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared as in Example 54, substituting R-4-carboxybutyrolactone for its N-BOC-L-alanine. The product was obtained as a pale yellow oil with a yield of 63%: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.88 (m, 1H), 7.37 (m, 1H), 6.86 (m, 1H), 4.86 (m, 1H) , 4.76(m, 1H); 4.60(m, 1H), 4.32(t, J=8Hz, 2H), 4.11(m, 1H), 2.50(m, 6H); MS(DCI/NH ₃ ) m/e 295; [α] _D ²⁰ +77.50° (c=0.16, dichloromethane); Anal. Calcd. for C ₁₄ H ₁₅ N ₂ O ₄ F·0.4 H ₂ O: C, 55.77; H, 5.28; N, 9.29 ; Found: C, 55.82; H, 5.34; N, 9.21.

Example 66

1-(2-(Hydroxymethyl)benzoyl) Prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared as in Example 54, substituting 2-hydroxymethylbenzoic acid for its N-BOC-L-alanine. The product was obtained as a light oily product with a yield of 44%: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.94 (m, 1), 7.37 (m, 5H), 6.87 (m, 1H), 4.90 (m, 1H), 4.71(m, 1H); 4.60(br d, J=11Hz, 1H), 4.43(br d, J=11Hz, 1H), 4.18(m, 2H), 3.99(m1), 2.50(m, 2H); MS (DCI/NH ₃ ) m/e 317, 200, 183, 169, 152; [α] _D ²⁰ -12.18° (c=0.12, dichloromethane); C ₁₇ H ₁₇ N ₂ O ₃ F·0.1H Anal. Calcd. for ₂ O: C, 64.18; H, 5.45; N, 8.81; Found: C, 64.24; H, 5.39; N, 8.73.

Example 67

1-(L-phenylalanyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

Add BF ₃ ·Et ₂ O (103mg, 1.0eq) to the 1-(N-BOC-L-phenylalanyl group of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine ) prodrug (from Example 57, 310 mg, 0.70 mmol) in dichloromethane (20 mg). The solution was stirred at room temperature for 1 hour, then quenched with 5% sodium bicarbonate and extracted into dichloromethane (100ml), dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by chromatography eluting with 10% methanol/dichloromethane. The product was obtained as a colorless oil with a yield of 53%: ¹ HNMR (300MHz, CDCl ₃ ) δ7.84 (m, 1H), 7.26 (m, 6H), 6.84 (dd, J=3, 9Hz, 1H), 4.53 (m, 1H), 4.46(dd, J=5, 10Hz, 1H), 4.16(dd, J=3, 10Hz, 1H), 3.93(q, J=8Hz, 1H), 3.42(m, 1H), 3.14(m, 1H), 2.91(dd, J=8, 13Hz, 1H), 2.82(dd, J=7, 13Hz, 1H), 2.23(m, 1H), 2.09(m, 1H): MS (DCI /NH ₃ ) m/e: 330, 120; [α] _D ²⁰ -52.71 ° (c=0.30, dichloromethane); Analytical calculated value for C ₁₈ H ₂₀ N ₃ O ₂ F·0.5H ₂ O: C , 63.86; H, 6.26; N, 12.42; Found: C, 63.77; H, 6.08; N, 12.40.

Example 68

1-(L-alanyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

According to the method of Example 67, by making the 1-(N-BOC-L-alanyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine (to obtain This compound was obtained from deprotection of Example 54). The product was obtained as a colorless oil with a yield of 26%: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.87 (m, 1H), 7.37 (m, 1H), 6.96 (dd, J=3, 9Hz, 1H), 4.69(m, 1H), 4.55(m, 1H), 4.20(m, 2H), 4.06(m, 1H), 3.38(q, J=7Hz, 1H), 2.47(m, 2H), 1.23(d, J=7Hz, 3H): MS (DCI/NH ₃ ) m/e: 254; [α] _D ²⁰ -31.62° (c=0.05, dichloromethane); C ₁₂ H ₁₆ N ₃ O ₂ F·1.15H Anal. Calcd. for ₂ O: C, 52.60; H, 6.73; N, 15.34; Found: C, 52.58; H, 6.56; N, 15.27.

Example 69

1-(D-phenylalanyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

According to the method of Example 67, by making 1-(N-BOC-D-phenylalanyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine ( Deprotection from Example 62) affords this compound. The product was obtained as a colorless oil in 53% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.84 (m, 1H), 7.35 (m, 1H), 7.22 (m, 5H), 6.87 (m, 1H) , 4.67(m, 1H), 4.31(m, 1H), 4.10(m, 2H), 3.6-4.0(m, 2H), 2.88(m, 2H), 2.40(m, 1H), 2.24(m, 1H ): MS (DCI/NH ₃ ) m/e 330; [α] _D ²⁰ +20.75° (c=0.27, dichloromethane); Anal. Calcd. for C ₁₈ H ₂₀ N ₃ O ₂ F·0.5H ₂ O : C, 63.89; H, 6.26; N, 12.42; Found: C, 63.92; H, 6.06; N, 12.48.

Example 70

1-(D-Alanyl) Prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

According to the method of Example 67, by making the 1-(N-BOC-D-alanyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine (to obtain This compound was obtained from deprotection of Example 63). The product was obtained as a colorless oil which was treated with 1 eq p-toluenesulfonic acid in ethanol to form the p-toluenesulfonate salt (17%) as a colorless semi-solid: ¹ H NMR (300 MHz, CD ₃ OD) δ7. 90m(1), 7.70(d, J=8Hz, 2H), 7.59(m, 1H), 7.23(d, J=8Hz, 2H), 7.00(dd, J=3, 9Hz, 1H), 4.76(m , 1H), 4.55(m, 1H), 4.39(m, 1H), 4.21(m, 2H), 4.02(m, 1H), 2.52(m, 2H), 2.37(s, 3H), 1.34(d, J=7Hz, 3H): MS (DCI/NH ₃ ) m/e: 254, 183, 141; [α] _D ²⁰ +11.10° (c=0.05, dichloromethane); C ₁₂ H ₁₆ N ₃ O ₂ Anal. _{Calcd. for F·C7H8O3S :} C, 52.42; H, 5.57; N, _7.64 ; Found: C, 53.31; H, 5.77; N, 7.34.

Example 71

1-(N-Succinimidylmethyl) Prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

5-(2R)-Azetidinylmethoxy)-2-fluoropyridine p-toluenesulfonate (from Example 8, 150 mg, 0.42 mmol) was mixed with succinimide (47 mg, 1.1 eq ) and potassium carbonate (88mg, 1.5eq). Ethanol (20ml) was added followed by aqueous formalin (36%, 110mg, 3.2eq). The mixture was stirred at 40-45°C for 2-3 hours, then cooled to 25°C and concentrated to a white solid. Purification by silica gel chromatography, eluting with 1% methanol/ethyl acetate, afforded the title compound (70 mg, 59%) as a colorless oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ7.86 (m, 1H), 7.41 (ddd, J=3, 6, 9Hz, 1H), 6.85 (dd, J=3, 9Hz, 1H), 4.34 (AB quartet, J=13Hz, 2H), 4.02 (m, 2H), 3.76 ( m, 1H), 3.43(dt, J=3, 8Hz, 1H), 3.24(m, 1H), 2.76(s, 4H), 2.11(m, 1H), 2.02(m, 1H): MS (DCI/ NH ₃ ) m/e: 294 ((M+1)), 183; Anal. Calcd. for C ₁₄ H ₁₆ N ₃ O ₃ F 0.5H ₂ O: C, 55.62; H, 5.67; N, 13.90; found Values: C, 55.76; H, 5.61; N, 13.92.

Example 72

1-(N-phthalimidomethyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

According to the method of Example 71, 5-(2R)-azetidinylmethoxy)-2-fluoropyridine p-toluenesulfonate (obtained from Example 8) and phthalimide Mix to obtain the title compound: mp97-100°C; ¹ H NMR (300MHz, CDCL ₃ ) δ7.88 (m, 1H), 7.76 (m, 3H), 7.33 (ddd, J=3, 6, 9Hz, 1H), 6.82(dd, J=3, 9Hz, 1H), 4.54(s, 2H), 4.05(m, 2H), 3.82(m, 1H), 3.45(m, 1H), 3.28(q, J=8Hz, 1H ), 2.13 (m, 1H), 2.00 (m, 1H); MS (DCI/NH ₃ ) m/e: 342 (M+1), 183; C ₁₈ H ₁₆ N ₃ O ₃ F·0.50H ₂ O Anal. Calcd for: C, 61.70; H, 4.89; N, 11.99; Found: C, 61.68; H, 4.93; N, 11.87.

Example 73

1-(N-(2-Hydroxybenzoyl)aminomethyl)prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

Following the procedure of Example 71, mixing 5-(2R)-azetidinylmethoxy)-2-fluoropyridine p-toluenesulfonate (from Example 8) with salicylamide gave the title compound : ¹ HNMR (300MHz, CDCl ₃ ) δ7.80(dd, J=2, 3Hz, 1H), 7.40(t, J=8Hz, 1H), 7.28(m, 2H), 6.99(d, J=8Hz, 1H), 6.78(m, 3H), 4.39(dd, J=6, 12Hz, 1H), 4.24(dd, J=5, 12Hz, 1H), 4.05(m, 2H), 3.80(m, 1H), 3.45(q, J=6Hz, 1H), 3.27(q, J=8Hz, 1H), 2.12(m, 2H); MS(DCI/NH ₃ ) m/e: 332((M+1)), 183 , 155, 138; Anal. Calcd. for C ₁₇ H ₁₈ N ₃ O ₃ F 0.50H ₂ O: C, 59.99; H, 5.62; N, 12.34; Found: C, 59.78; H, 5.67; N, 12.06 .

Example 74

1-(2,5-Dihydro-2-oxo-furan-4-yl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

5-(2R)-azetidinylmethoxy)-2-fluoropyridine p-toluenesulfonate (from Example 8, 200mg, 0.56mmol) was mixed with tetronic acid (84mg, 1.5eq) And a mixture of potassium carbonate (77mg, 1eq) and absolute ethanol was heated in a sealed test tube at 40-45°C for 2-3 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The product was purified by silica gel chromatography, eluting with 2% methanol/dichloromethane, to provide the title compound (86 mg, 56%): mp 93°C (ethyl acetate/ether); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.85 ( dd, J=2, 3Hz, 1H), 7.36(ddd, J=3, 6, 9Hz, 1H), 6.90(dd, J=3, 9Hz, 1H), 4.67(m, 4H), 4.1 8(m , 2H), 4.08.dt(5, J=9Hz, 1H), 3.95(m, 1H), 2.68(m, 1H), 2.39(m, 1H); MS(APCI) m/e265((M+1 )); Anal. Calcd. for _{C13H16N2O3F :} C, 59.08; H, 4.95 _{; N} , 10.60; Found: C, 58.90; H, 4.88; N, 10.52.

Example 75

1-(5,5-Dimethyl-3-oxohexenyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

According to the method of Example 74, by reaction with 5,5-dimethyl-1,3-cyclohexanedione, from 5-(2R)-azetidinylmethoxy)-2-fluoro The title compound was prepared from pyridine p-toluenesulfonate (from Example 8) in 65% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.85 (dd, J=2, 3 Hz, 1H), 7.35 (ddd , J=3, 6, 9Hz, 1H), 6.87(dd, J=3, 9Hz, 1H), 5.02(m, 1H), 4.62(m, 1H), 4.29(m, H), 4.15(m, 1H), 4.05(m, 1H), 3.91(m, 1H), 2.59(m, 1H), 2.37(m, 1H), 2.14(br s, 2H), 2.09(m, 2H), 1.05(s, 3H), 1.03 (s, 3H); MS (DCI/NH ₃ ) m/e 305 ((M+1)); Anal. Calcd. for C ₁₇ H ₂₁ N ₂ O ₂ F·0.75H ₂ O: C, 64.23; H, 7.13; N, 8.81; Found: C, 63.89; H, 7.03; N, 8.73.

Example 76

1-(3-oxocyclohexenyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

According to the method of Example 74, by reaction with 5,5-dimethyl-1,3-cyclohexanedione, from 5-(2R)-azetidinylmethoxy)-2-fluoro The title compound was prepared from pyridine p-toluenesulfonate (from Example 8) in 77% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.84 (dd, J=2, 3 Hz, 1H), 7.35 (ddd , J=3, 6, 9Hz, 1H), 6.87(dd, J=3, 9Hz, 1H), 5.01(m, 1H), 4.61(m, 1H), 4.26(m, 1H), 4.13(m, 1H), 4.04(m, 1H), 3.92(m, 1H), 2.58(m, 1H), 2.37(m, 1H), 2.27(m, 4H), 1.94(m, 2H); MS(DCI/ NH ₃ ) m/e 277 ((M+1)); Anal. Calcd. for C ₁₅ H ₁₇ N ₂ O ₂ F 0.75 H ₂ O: C, 62.16; H, 6.43; N, 9.66; Found: C , 62.15; H, 6.30; N, 9.67.

Example 77

1-(2,2-Bis(ethoxycarbonyl)vinyl)prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

According to the method of Example 74, from 5-(2R)-azetidinylmethoxy)-2-fluoro Pyridine p-toluenesulfonate (from Example 8) prepared the title compound in 81% yield: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.85 (m, 1H), 7.67 (br s, 1H), 7.36 ( ddd, J=3, 6, 9Hz, 1H), 6.87(dd, J=3, 9Hz, 1H), 4.79(m, 1H), 4.29(m, H), 4.17(m, 6H), 4.02(m , 1H), 2.58(m, 1H), 2.26(m, 1H), 1.30(t, J=7Hz, 3H), 1.26(t, J=7Hz, 3H); MS(DCI/NH ₃ ) m/e 353 (M+1); Anal. Calcd. _{for C17H21N2O5F} : C, 57.94; H, 6.00; N, 7.95; Found _{: C} , 57.63;

Example 78

1-(Ethoxycarbonyl) Prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

To a solution of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine p-toluenesulfonate (obtained from Example 8, 0.2g, 0.56mmol) in dichloromethane (10ml) and Ethyl chloroformate (0.064 g, 0.59 mmol) was added to 10 ml of sodium bicarbonate solution. The reaction mixture was stirred at room temperature for 2 hours. The organic layer was separated, dried (magnesium sulfate) and evaporated. The residue was chromatographed on silica gel, eluting with 1:1 ethyl acetate:hexanes, to afford 0.09 g (63%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.87 (m, 1H), 7.28 ( ddd, J=3, 6, 9Hz, 1H), 6.86(dd, J=3, 9Hz, 1H), 4.59(m, 1H), 4.26(m, 1H), 4.14(m, 1H), 4.10(q , J=7Hz, 2H), 3.96(t, J=3, 8Hz, 1H), 2.38(m, 2H), 1.22(t, J=7Hz, 3H); MS(DCI/NH ₃ ) m/e: 255; _Anal. Calcd. for _C12H15N2O3F - _0.5H2O : C, _56.69 ; H, _5.95 ; N, 11.02; Found: C, 56.40; H, 5.78;

Example 79

1-(phenoxycarbonyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared from 5-(2R)-azetidinylmethoxy)-2-fluoropyridine p-toluenesulfonate (from Example 8) according to the method of Example 78, but with chloro Phenyl formate replaced its ethyl chloroformate, yield 83%: ¹ HNMR (300MHz, CDCl ₃ ) δ7.90 (dd, J=2, 3Hz, 1H), 7.35(m, 3H), 7.18(m, 1H), 7.06(br d, J=8Hz, 2H), 6.86(dd, J=3, 9Hz, 1H), 4.73(m, 1H), 4.46(dd, J=4, 10Hz, 1H), 4.12( m, 3H), 2.48 (m, 2H); MS (DCI/NH ₃ ) m/e: 303; Anal. Calcd. for C ₁₆ H ₁₅ N ₂ O ₃ F: C, 63.57; H, 5.00; N, 9.27 ; Found: C, 63.82; H, 4.86; N, 8.99.

Example 80

1-(4-nitrophenoxycarbonyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared from 5-(2R)-azetidinylmethoxy)-2-fluoropyridine p-toluenesulfonate (from Example 8) according to the method of Example 78, but with 4- Nitrophenyl chloroformate replaced its ethyl chloroformate, yield 82%: mp68-70℃; ¹ H NMR (300MHz, CDCl ₃ ) δ8.22(m, 2H), 7.91(m, 1H ), 7.39(ddd, J=3, 6, 9Hz, 1H), 7.27(m, 2H), 6.88(dd, J=3, 9Hz, 1H), 4.76(m, 1H), 4.47(m, 1H) , 4.19 (m, 3H), 2.52 (m, 2H); MS ( _DCI /NH ₃ ) m/e: 348; [α] _D ²⁰ 11.18° (c=0.004, _{dichloromethane} ); Anal. Calcd. for ₃ O ₅ F: C, 55.33; H, 4.06; N, 12.10; Found: C, 54.95; H, 4.00; N, 11.96.

Example 81

1-(4-methoxyphenoxycarbonyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared from 5-(2R)-azetidinylmethoxy)-2-fluoropyridine p-toluenesulfonate (from Example 8) according to the method of Example 78, but with 4- Methoxyphenyl chloroformate replaced its ethyl chloroformate, yield 65%: mp60-61℃; ¹ H NMR (300MHz, CDCl ₃ ) δ7.90(m, 1H), 7.40(ddd, J=3, 6, 9Hz, 1H), 6.97(br d, J=9Hz, 2H), 6.86(m, 3H), 4.72(m, 1H), 4.46(dd, J=4, 10Hz, 1H), 4.15 (m, 3H), 3.77 (s, 3H), 2.48 (m, 2H); MS (DCI/NH ₃ ) m/e: 333; [α] _D ²⁰ 9.11° (c=.0047, dichloromethane ); _{Anal. Calcd} . for _{C17H17N2O4F :} C, 61.44; H, 5.16; N, 8.43; Found: C, 61.39; H, 5.11; N, 8.22.

Example 82

1-(4-methoxycarbonyl)phenoxycarbonyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared from 5-(2R)-azetidinylmethoxy)-2-fluoropyridine p-toluenesulfonate (from Example 8) according to the method of Example 78, but with 4- (Methoxycarbonyl)phenyl chloroformate replaced its ethyl chloroformate, yield 84%: mp 90-92°C; ¹ HNMR (300MHz, CDCl ₃ ) δ8.13 (m, 2H), 7.9 (m, 1H), 7.4(m, 1H), 7.15(d, 2H), 6.88(dd, 1H), 4.73(m, 1H), 4.48(m, 1H), 4.1 8(m, 3H), 3.9 (s, 3H), 2.5 (m, 2H); MS (CI/NH ₃ ) m/e: 361 (M+1), 378 (M+NH ₄ ).

Example 83

1-(4-methoxyphenoxycarbonyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared from 5-(2R)-azetidinylmethoxy)-2-fluoropyridine p-toluenesulfonate (from Example 8) according to the method of Example 78, but with 4- Methylphenyl chloroformate replaced its ethyl chloroformate, yield 96%: mp 68-70°C; ¹ H NMR (300MHz, CDCl ₃ ) δ7.9(m, 1H), 7.4(m, 1H), 7.12(d, 2H), 6.93(d, 2H), 6.86(dd, 1H), 4.71(m, 1H), 4.45(m, 1H), 4.13(m, 3H), 2.47(m, 2H ), 2.3 (s, 3H); MS (CI/NH ₃ ) m/e: 317 (M+1), 334 (M+NH ₄ ).

Example 84

1-(4-fluorophenoxycarbonyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared from 5-(2R)-azetidinylmethoxy)-2-fluoropyridine p-toluenesulfonate (from Example 8) according to the method of Example 78, but with 4- Fluorophenyl chloroformate replaced its ethyl chloroformate, yield 72%: ¹ H NMR (300MHz, CDCl ₃ ) δ7.9(m, 1H), 7.4(m, 1H), 7.2(d , 4H), 6.88(dd, 1H), 4.73(m, 1H), 4.48(m, 1H), 4.18(m, 3H), 2.5(m, 2H); MS(CI/NH ₃ ) m/e: 321 (M+1), 338 (M+ _NH4 ).

Example 85

1-(4-Chlorophenoxycarbonyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared from 5-(2R)-azetidinylmethoxy)-2-fluoropyridine p-toluenesulfonate (from Example 8) according to the method of Example 78, but with 4- Chlorophenyl chloroformate replaced its ethyl chloroformate, yield 85%: ¹ H NMR (300MHz, CDCl ₃ ) δ7.9(m, 1H), 7.4(m, 1H), 7.3(m , 2H), 7.02(m, 2H), 6.87(dd, 1H), 4.73(m, 1H), 4.47(m, 1H), 4.17(m, 3H), 2.5(m, 2H); MS(CI/ NH ₃ ) m/e: 337 (M+1), 354 (M+NH ₄ ).

Example 86

1-(2,6-Dimethylphenoxycarbonyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared from 5-(2R)-azetidinylmethoxy)-2-fluoropyridine p-toluenesulfonate (from Example 8) according to the method of Example 78, but with 2, 6-Dimethylphenyl chloroformate replaced its ethyl chloroformate, yield 43%: ¹ H NMR (300MHz, CDCl ₃ ) δ7.9(m, 1H), 7.4(m, 1H), 7.03(s,3H), 6.88(dd,1H), 4.73(m,1H), 4.5(m,1H), 4.18(m,3H), 2.5(m,2H), 2.15(bs,6H); MS (CI/NH ₃ ) m/e: 331 (M+1), 348 (M+NH ₄ ).

Example 87

1-(2-methylphenoxycarbonyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared in quantitative yield from 5-(2R)-azetidinylmethoxy)-2-fluoropyridine p-toluenesulfonate (from Example 8) following the procedure of Example 78 , as a colorless oil, but its ethyl chloroformate was replaced by 2-methylphenyl chloroformate: ¹ H NMR (CDCl ₃ ) δ 8.13 (m, 2H), 7.9 (m, 1H) , 7.4(m, 1H), 7.15(d, 2H), 6.88(dd, 1H), 4.73(m, 1H), 4.5(m, 1H), 4.18(m, 3H), 2.5(m, 2H), 2.15 (s, 3H); MS (CI/NH ₃ ) m/e: 317 (M+1), 334 (M+NH ₄ ).

Example 88

1-(1-Acetoxy-1-methyl)ethoxycarbonyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

88a. p-Nitrophenyl propylene carbonate

Isopropyl chloroformate (5.0 g, 41.5 mmol) was added to an ice-cold suspension of p-nitrophenol (6.3 g, 45.6 mmol) in chloroform (100 mL). To the stirred reaction mixture was added pyridine (3.32 g, 41.5 mmol) dropwise over 20 minutes. After stirring for 15 minutes at ice bath temperature, the reaction mixture was allowed to warm and stirred at room temperature for 16 hours. The reaction mixture was washed with water, 1N hydrochloric acid, ice-cold aqueous 1% sodium hydroxide, water and brine. The organic layer was dried (magnesium sulfate) and the solvent was evaporated. Subsequent crystallization of the solid residue from hexane provided the title compound (7.8 g, 84% yield): ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.05 (s, 3H), 4.82 (t, 1H, J = 1.0 Hz), 4.96 (d, 1H, J = 1.0 Hz), 7.40-7.46 (m, 2H), 8.27-8.32 (m, 2H).

88b. 2-Chloro-2-propyl p-nitrophenyl carbonate

Propylene carbonate (7.5 g, 33.6 mmol) from Step 88a was dissolved in a mixture of diethyl ether (100 mL) and chloroform (100 mL). The mixture was cooled to 0°C, then hydrogen chloride gas was bubbled through. After standing at room temperature for 16 hours, nitrogen was bubbled through the mixture to remove excess HCl, and the solvent was evaporated to give the title compound (8.0 g, 92%): ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.11 (s, 6H ), 7.39-7.44 (m, 2H), 8.27-8.32 (m, 2H).

88c. 2-Acetoxy-2-propyl p-nitrophenyl carbonate

A mixture of 2-chloro-2-propyl p-nitrophenyl carbonate (8.0 g, 30.8 mmol) and mercuric acetate (11.0 g, 34.6 mmol) in dichloromethane (400 ml) was stirred at room temperature for 72 Hour. The reaction mixture was washed with brine containing a few drops of sodium bicarbonate solution, then with sodium bicarbonate solution. The organic layer was dried (magnesium sulfate) and evaporated to an oil (5.4 g, 62%). ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.93 (s, 6H), 2.10 (s, 3H), 7.37-7.42 (m, 2H), 8.26-8.31 (m, 2H).

88d.1-(1-acetoxy-1-methyl)ethoxycarbonyl)prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

3-(2-(R)-Azetidinylmethoxy)-6-fluoro-pyridine (from Example 8, 0.30 g, 1.65 mmol) and 2-acetoxy A solution of 2-propyl-p-nitrophenyl carbonate (0.49g, 1.73mmol) in dimethylformamide (6ml) was stirred at room temperature for 24 hours. The reaction mixture was diluted with water (25ml) and extracted with ethyl acetate. The organic layer was washed with water, 1% ice-cold aqueous solution of sodium hydroxide, 1N hydrochloric acid, water and brine, then dried (magnesium sulfate) and concentrated. The residue was chromatographed to give a pale yellow oil (0.175 g, 33%). ¹ H NMR (300MHz, CDCl ₃ ) δ7.88(s, 1H), 7.40(m, 1H), 6.86(dd, J=3.7, 8.8Hz, 1H), 4.57(m, 1H), 4.34(m, 1H), 4.14(m, 3H), 3.95(t, J=7.5Hz, 2H), 2.34-2.44(m, 2H), 2.01(s, 3H), 1.98(s, 3H), 1.79(s, 3H ); MS (DC/NH ₃ ) m/e: 327 ((M+1)); [α] _D ²⁰ +74.5° (c=0.2, methanol); Calculation for C ₁₅ H ₁₉ N ₂ O ₅ F Values: C, 54.81; H, 5.60; N, 8.26; Found: C, 55.21; H, 5.87; N, 8.58.

Example 89

1-((5-methyl-2-oxo-1,3-dioxol-4- (en-4-yl)methoxycarbonyl)prodrug

A sample of 5-(2R)-azetidinylmethoxy-2-fluoropyridine (from Example 8 (0.13 g, 0.7 mmol)) and (5-methyl -2-oxo-1,3-dioxol-4-en-4-yl)methyl p-nitrophenyl carbonate (according to J.Alexander et al., J.Med.Chem.1996, 39, prepared from 480-486) 0.21 g, 0.73 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, 1N hydrochloric acid, 2% sodium carbonate and brine. Dried over magnesium sulfate and evaporated. Chromatography of the residue on silica gel eluting with 30% ethyl acetate/hexanes afforded 0.17 g (72%) of product: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.86 (m, 1H), 7.36 (ddd , J=3, 6, 9Hz, 1H), 6.87(dd, J=3, 9Hz, 1H), 4.80(m, 2H), 4.61(m, 1H), 4.36(m, 1H), 4.11(dd J =3,10Hz,1H), 3.99(m,2H), 2.42(m,2H), 2.15(s,3H); MS(DCI/NH ₃ ) m/e: 339,183; [α]D ²⁰ + 6.43° (C=0.0042, _CH2Cl2 ) _, Anal. _Calcd . _{for C15H15N2O6F} : C, 53.26 _; H, 4.47; N, 8.28; Found: C, 53.52; H, 4.58; N, 8.15.

Example 90

1-((5-methyl-2-oxo-1,3-dioxol-4- (en-4-yl)methoxycarbonyl)prodrug

The title compound was prepared from 5-(2R)-azetidinylmethoxy)-2-fluoropyridine (from Example 8) according to the method of Example 450, except that (5-phenyl-2 -Oxo-1,3-dioxolan-4-ylmethyl p-nitrophenyl carbonate (J.Alexander et al., J.Med.Chem.1996,39,480-486) instead of (5 -Methyl-2-oxo-1,3-dioxol-4-en-4-yl)methyl p-nitrophenyl carbonate, yield 61%: ¹ H NMR (300MHz, CDCl ₃ ) δ7.85(m, 1H), 7.59(m, 2H), 7.44(m, 3H), 7.35(m, 1H), 6.84(dd J=3, 9Hz, 1H), 5.09(m, 2H ), 4.63(m, 1H), 4.37(m, 1H), 4.11(dd J=3, 10Hz, 1H), 4.03(m, 2H), 2.44(m, 2H); MS(CI/NH ₃ )m /e: 401,194; [α] _D ²⁰ +3.07° (c=0.0035, dichloromethane); Anal. Calcd. for C ₂₀ H ₁₇ N ₂ O ₆ F: C, 60.00; H, 4.28; N, 7.00 ; Found: C, 59.81; H, 4.30; N, 6.98.

Example 91

1-((pyrrolidin-1-yl)carbonyl)prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

5-(2R)-azetidinylmethoxy-2-fluoropyridine (from Example 8, 0.09 g, 0.49 mmol) and pyrrolidinecarbonyl chloride (0.073 g) in toluene (10 ml) , 0.54mmol) solution was refluxed for 5 hours. The reaction mixture was evaporated and partitioned between dichloromethane/water. The organic layer was dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate to give 0.07 g (51%) of the product: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.86 (m, 1H), 7.38 (m, 1H), 6.85 ( m, 1H), 4.5-4.8(m, 2H), 3.8-4.2(m, 3H), 3.33(m, 4H), 2.36(m, 2H), 1.84(m, 4H); MS(DCI/NH ₃ ) m/e: 280, 169; [α] _D ²⁰ +6.57° (c=0.0026, dichloromethane); Anal. Calcd. for C ₁₄ H ₁₈ N ₃ O ₂ F·0.75H ₂ O: C, 57.42; H, 6.71; N, 14.35; Found: C, 57.51; H, 6.43; N, 14.36.

Example 92

1-((pyrrolidin-1-yl)carbonyl)prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared from 5-(2R)-azetidinylmethoxy)-2-fluoropyridine (from Example 8) following the procedure of Example 91 but substituting diethylcarbamoyl chloride Its pyrrolidine carbonyl chloride, yield 46%: ¹ H NMR (300MHz, CDCl ₃ ) δ7.87 (m, 1H), 7.39 (ddd, J=3, 6, 9Hz, 1H), 6.82 (dd, J= 3, 9Hz, 1H), 4.72(m, 1H), 4.20(ddJ=5, 10Hz, 1H), 4.10(dd, J=3, 10Hz, 1H), 3.96(m, 1H), 3.84(m, 1H ), 3.18(m, 4H), 2.33(m, 2H), 1.09(t, J=7Hz, 6H); MS(DCI/NH ₃ ) m/e: 282; [α] _D ²⁰ +2.66°(c = 0.005, _{dichloromethane} ); Anal. Calcd. for _{C14H20N3O2F :} C, _59.77 ; H, 7.17; N, 14.94; Found: C, 59.65; H, 7.04; N, 14.90.

Example 93

1-(acetyl)prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

Under nitrogen, 5-(2R)-azetidinylmethoxy-2-fluoropyridine (from Example 8, 162 mg, 0.89 mmol), acetic anhydride (0.12 ml, 1.26 mmol), TEA (0.2ml, 1.47mmol) and dichloromethane (30ml) were combined and stirred for 16 hours. The solution was extracted with saturated aqueous sodium carbonate (30ml), brine (2x30ml) and dried (magnesium sulfate). The solvent was evaporated in vacuo, and the crude product was chromatographed (silica gel, hexane/ethyl acetate 9:1-7:3) to obtain 160 mg (80%) of the title compound: ¹ H NMR (DMSO-d ₆ , 300 MHz) δ1.74 ( s, 3H), 2.16 (m, H), 2.40 (m, 1H), 3.86 (br s, 2H), 4.25 (dd J = 3.5, 10.5, 1H), 4.36 (d, J = 4.5, 10.5, 1H ), 4.58 (br s, 1H), 7.01 (dd, J=3.5, 8.5, 1H), 7.57 (m, 1H), 7.90 (m, 1H); MS (CI/NH ₃ ) m/e: 225 ( M+H) ⁺ 242(M+NH ₄ ) ⁺ ; [α] _D +91.7° (c1, MeOH); Anal. Calcd. for C ₁₁ H ₁₃ FN ₂ O ₂ 0.2C ₄ H ₈ O ₂ : C, 58.6; H, 6.08; N, 11.58; Found: C, 58.27; H, 6.04; N, 11.63.

Example 94

1-(tert-butoxycarbonyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

At room temperature, 5-(2R)-azetidinylmethoxy-2-fluoropyridine (from Example 8, 0.12 g, 0.7 mmol), di-tert-butyl dicarbonate (0.23 g, 1 mmol) and DMAP (0.13 mL, 1 mmol) in dichloromethane (10 mL) were stirred for 16 hours. The mixture was evaporated and the residue was chromatographed on silica gel eluting with ethyl acetate/hexane 1:1 to give 0.14 g (71%) of the product: ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.87 (m, 1H), 7.38(ddd, J=3, 6, 9Hz, 1H), 6.85(dd, J=3, 9Hz, 1H), 4.50(m, 1H), 4.31(m, 1H), 4.12(dd J=3, 10Hz , 1H), 3.89 (t, J=8Hz, 2H), 2.33 (m, 2H), 1.42 (s, 9H); MS (DCI/NH ₃ ) m/e: 283, 227; C ₁₄ H ₁₉ N ₂ Anal. Calcd. for _O3F : C, 59.56; H, 6.78; N, 9.92; Found: C, 59.34; H, 6.65; N, 9.88.

Example 95

Bisulfite prodrug of 1-(3-thiopropanoyl)5-(2R)-azetidinylmethoxy)-2-fluoropyridine

To a solution of 3,3'-dithiodipropionic acid (100mg, 0.48mmol) and triethylamine (53mg, 0.53mmol) in THF (1.0ml) was added dropwise isochloroformic acid under stirring at -78°C. Butyl ester (68 mg, 0.51 mmol). After stirring at -78°C for 1 hour, 5-(2R)-azetidinylmethoxy-2-fluoropyridine (from Example 8, 175 mg, 0.96 mmol) was added to the reaction mixture. The resulting solution was warmed to 25°C and stirred for 3 hours. After all starting material was consumed, the organic solvent was evaporated in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (1:1) to give the title compound (102 mg, 21%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.32-2.65 (m, 8H), 2.79-2.97(m, 4H), 3.89-4.27(m, 6H), 4.50(dd J=4.4Hz, 9.8H, 2H), 4.61-4.83(m, 1H), 6.85(dd, J= 3.8Hz, 8.2H, 2H), 7.37(m, 2H), 7.87(m, 2H); MS(CI/NH ₃ ) m/e: 539(M+1); [α] _D ²⁰ +101°( c=0.10, MeOH); Anal _. Calcd. for _{C24H28N4O2F2S2.0.5CHCl3 :} C, _51.96 ; H, _5.07 ; N _{, 9.89} ; Found: C, 52.13; H, 5.40 ; N, 10.25.

Example 96

1-(S-(phenylmethyl)cysteinoyl) (cysteinoyl) prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

To a THF solution of S-benzyl-N-Cbz-(L)-cysteine and triethylamine was added dropwise isobutyl chloroformate at -78°C under stirring. After stirring at -78°C for 1 hour, 5-(2R)-azetidinylmethoxy-2-fluoropyridine (from Example 8, 175 mg, 0.96 mmol) was added to the reaction mixture. The resulting solution was warmed to 25°C and stirred for 3 hours. After all starting material was consumed, the organic solvent was evaporated in vacuo. The residue was purified by N-deprotection and silica gel column chromatography, eluting with ethyl acetate: hexane (1:1) to give the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ7.16-7.40 (m, 6H), 7.86(m, 1H), 6.84(m, 1H), 4.66(m, 1H), 4.51(m, 1H), 4.04-4.22(m, 2H), 3.96(m, 1H), 3.75(s , 2H), 3.38(m, 1H), 2.74(m, 1H), 2.58(m, 1H), 2.34-2.48(m, 2H), 1.63-2.04(m, 2H); MS(DCI/NH ₃ ) m/e: 376 (M+H) ⁺ ; [α] _D ²⁰ +110° (c=0.05, MeOH); Anal. Calcd. for C ₁₉ H ₂₂ N ₃ O ₂ FS·0.1 H ₂ O: C, 60.49 H, 5.93; N, 11.14; Found: C, 60.11; H, 6.01; N, 10.80.

Example 97

2-Chloro-3-(2-(R)-azetidinylmethoxy)pyridine p-toluenesulfonate

97a. 2-Chloro-3-(1-Boc-2-(R)-azetidinylmethoxy)pyridine

Following the procedure of Examples 10c and 10d, but substituting Boc-(R)-hydroxymethylazetidine for the Boc-(S)-hydroxymethylazetidine used in step 10c, 2-chloro Di-3-hydroxypyridine was used in place of 3-chloro-5-hydroxypyridine used in step 10d. The title compound was obtained as an oil (535 mg, 93%): ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.40 (s, 9H), 2.40 (m, 2H), 3.90-4.00 (m, 2H), 4.16 (m , 1H), 4.55(m, 2H), 7.20(m, 1H), 7.35(m, 1H); 8.00(m, 1H); MS(CI/NH ₃ ) m/e: 299(M+1) ⁺ .

97b. 2-Chloro-3-(2-(R)-azetidinylmethoxy)pyridine p-toluenesulfonate

The product of Example 459a was worked up according to the method of Example 407b. Chromatography (silica gel, chloroform/methanol, 95:5-90:10) of the residue afforded the free base of the title compound as a white solid, which was converted to a salt by treatment with p-toluenesulfonic acid in ethanol to afford the title compound. Compound (398 mg). mp 102-104 °C; [α] ²⁵ _D = +5.78 ° (c = 0.74, MeOH); ¹ H NMR (DMSO, 300 MHz) δ 2.28 (s, 3H), 2.52 (m, 2H), 2.62 (m , 1H), 3.98(m, 2H), 4.42(d, J=3Hz, 2H), 4.78(br, 1H), 7.18(d, J=9Hz, 2H), 7.45(d, J=6Hz, ,1H ), 7.52 (d, J=9Hz, 2H), 7.64 (dd, J=3, 9Hz, 1H), 8.05 (dd, J=3, 6Hz, 1H), 8.90 (br, 1H); MS (APCI) m/z: 199 (M+H) ⁺ , 231 (M+H+MeOH) ⁺ . _Anal. Calcd. for _C9H11ClN2O · _1.2TsOH · _0.5H2O : C, 50.45; H, 5.25; N, 6.76; Found: C, 50.30; H, 5.15; N, 6.56.

Example 98

6-Fluoro-3-(1-methyl-2-(R)-azetidinylmethoxy)pyridine p-toluenesulfonate

98a.1-Cbz-2-(R)-Azetidinylmethyl-p-toluenesulfonate

At 0°C, to a solution of 1-Cbz-2-(R)-azetidinylmethanol (30.76g, 218.8mmol) in dichloromethane (75ml) was added triethylamine (25.2ml, 179mmol) and p-toluene Sulfonyl chloride (34.46 g, 181 mmol). The mixture was stirred for 16 hours, filtered and the filtrate was washed with 2N sodium hydroxide (50ml), 2N hydrochloric acid (50ml), brine and dried (magnesium sulfate). The solvent was evaporated in vacuo, and the crude product was chromatographed (silica gel; hexane/ethyl acetate, 9:1-6:4) to obtain 44.1 g (78.8%) of the title compound: ¹ H NMR (CDCl ₃ , 300 MHz) δ2.21 -2.43(m, 3H), 2.45(s, 3H), 3.84-3.92(m, 2H), 4.13(m, 1H), 4.36(m, 1H), 4.58(m, 1H), 5.0(br.s 2H), 7.26-7.27 (m, 7H). MS (CI/NH ₃ ) m/e: 376 (M+H) ⁺ 393 (M+NH ₄ ) ⁺ . _Anal. Calcd. for _C19H21NO5S : C, 60.78; H, 5.64; N, 3.73; Found: C _, 60.40; H, 5.82; N, 3.75. [α] _D = +53.75 (c1.0, CHCl ₃ ).

98b.6-Fluoro-3-(1-Cbz-2-(R)-azetidinylmethoxypyridine

Following the procedure of Example 10d, but substituting the product of Step 98a for tert-butoxycarbonyl-(S)-tosyloxymethylazetidine and 2-fluoro- 5-hydroxypyridine instead of 3-fluoro-5-hydroxypyridine. The product was obtained as a colorless oil: ¹ H NMR (dmso-d ₆ , 300 MHz) δ 2.21 (m, 1H), 2.38 (m, 1H), 3.87 (t, J=7Hz, 2H), 4.19 (dd, J =4, 11Hz, 1H), 4.34(dd, J=4, 11Hz, 1H), 4.54(m, 1H), 5.01(m, 2H), 6.97(dd, J=3, 9Hz, 1H), 7.28( m, 5H), 7.50 (m, 1H), 7.85 (m, 1H). MS (CI/NH ₃ ) m/e: Anal. Calcd. for 317 (M+H) ⁺ C ₁₇ H ₁₇ FNO ₃ : C, 64.55; H, 5.42; N, 8.86; Found: C, 64.57; H, 5.44; N, 8.83. [α] _D +74.6° (c1.1, _CHCl3 ).

98c.6-Fluoro-3-(1-methyl-2-(R)-azetidinylmethoxy)pyridine p-toluenesulfonate

6-Fluoro-3-(1-Cbz-2-(R)-azetidinylmethoxypyridine (1 g, 3.16 mmol) from Example 98b was mixed with 10% Pd-C (50 mg) and paraformaldehyde (1 g) were mixed in ethanol (10 ml), and the mixture was stirred under hydrogen (1 atm) for 16 hours. The mixture was filtered and concentrated. The residue was dissolved in ethyl acetate and treated with p-toluenesulfonic acid to make Crystallization of the resulting salt from ethyl acetate-ether provided the title compound (813 mg, 74%): mp 121-125°C; ¹ H NMR (500 MHz, D ₂ O) δ 7.91 (m, 1H), 7.69 (d, J= 8.4Hz, 2H), 7.66(m, 1H), 7.37(d, J=7.9Hz, 2H), 7.10(dd, J=2.7, 8.6Hz, 1H), 4.86(m, 1H), 4.45(dd, J=2.4, 11.6Hz, 1H), 4.37(dd, J=5.5, 11.6Hz, 1H), 4.27(m, 1H), 4.00(q, J=10.2Hz, 1H), 2.99(s, 3H), 2.67 (m, 1H), 2.62 (m, 1H), 2.40 (s, 3H); ¹⁹ F NMR (471 MHz, D ₂ O) δ-78.38; MS (CI/NH ₃ ) m/e 197 (M+H ) ⁺ ; _Anal . _Calcd . for _C17H21N2O4FS : C, 55.42; H, 5.75; _N , 7.60; Found: C, 55.07; H, 5.79; N, 7.40.

Example 99

6-Fluoro-3-(1-ethyl-2-(R)-azetidinylmethoxy)pyridine p-toluenesulfonate

According to the method of Example 98c, but using acetaldehyde instead of paraformaldehyde, the title compound was prepared in 27% yield: mp106-109°C; ¹ H NMR (500MHz, D ₂ O) δ7.91 (m, 1H), 7.69 (d J = 8.0Hz, 2H), 7.66 (m, 1H), 7.37 (d, J = 7.9Hz, 2H), 7.11 (dd, J = 2.8, 8.4Hz, 1H), 4.82 (m, 1H), 4.43(m, 2H), 4.23(m, 1H), 3.98(q, J=9.7Hz, 1H), 3.42(m, 1H), 3.30(m, 1H), 2.64(m, 2H), 2.40(s , 3H), 1.24 (t, J=7.3Hz, 3H); ¹⁹ F NMR (471MHz, D ₂ O) δ-78.38; MS (CI/NH ₃ ) m/e 211 (M+H) ⁺ ; C _{18 Anal. Calcd} . for _H23N2O4FS : C, 56.53; H, 6.06; N, 7.32; Found: C, 56.28; H, 5.97; N, 7.20.

Example 100

6-Fluoro-3-(1-propyl-2-(R)-azetidinylmethoxy)pyridine p-toluenesulfonate

According to the method of Example 98c, but using propionaldehyde instead of paraformaldehyde, the title compound was prepared in 40% yield: mp93-95°C; ¹ H NMR (500MHz, D ₂ O) δ7.92 (m, 1H), 7.70 (d, J=8.5Hz, 2H), 7.66(m, 1H), 7.38(d, J=8.0Hz, 2H), 7.11(dd, J=2.5, 9.2Hz, 1H), 4.84(m, 1H) , 4.44(m, 2H), 4.23(m, 1H), 4.01(m, 1H), 3.34(m, 1H), 3.20(m, 1H), 2.63(q, J=8.5Hz, 2H), 2.40( s, 3H), 1.66 (m, 2H), 0.96 (t, J=7.8Hz, 3H); ¹⁹ F NMR (471 MHz, D ₂ O) δ-78.35; MS (CI/NH ₃ ) m/e 225 ( ^Anal . _Calcd . for _{C19H25N2O4FS :} C, 57.56; H, 6.36; _N , 7.07; Found: C, 57.37; H, 6.13; N, 6.82.

Example 101

6-Fluoro-3-(1-(1-methylethyl)-2-(R)-azetidinylmethoxy)pyridine p-toluenesulfonate

According to the method of Example 98c, but using acetone instead of paraformaldehyde, the title compound was prepared in 22% yield: mp93-95°C; ¹ H NMR (500 MHz, D ₂ O) δ7.88 (m, 1H), 7.68 ( d, J=8.4Hz, 2H), 7.64(m, 1H), 7.35(d, J=7.9Hz, 2H), 7.09(dd, J=2.6, 8.5Hz, 1H), 4.85(m, 1H), 4.39(m, 2H), 4.14(m, 1H), 4.02(q, J=9.5Hz, 1H), 3.58(sept., J=6.7Hz, 1H), 2.58(m, 2H), 2.38(s , 3H), 1.31(d, J=6.7Hz, 3H), 1.25(d, J=6.7Hz, 3H); ¹⁹ F NMR (471MHz, D ₂ O) δ-78.42; MS(CI/NH ₃ )m /e 225(M+H) ⁺ ; Anal _. Calcd. for _{C19H25N2O4FS.0.1CH3OH :} C, 57.19; H, 6.29 _; N, _6.77 ; Found: C, 56.98; H, 6.38; N, 6.94.

Example 102

6-Fluoro-3-(1-butyl)-2-(R)-azetidinylmethoxy)pyridine p-toluenesulfonate

According to the method of Example 98c, but using the starting material butyraldehyde instead of paraformaldehyde, the title compound was prepared in 83% yield: mp93-97°C; ¹ H NMR (500MHz, D ₂ O) δ7.91 (m, 1H), 7.69 (d, J=8.1Hz, 2H), 7.65(m, 1H), 7.37(d, J=8.5Hz, 2H), 7.10(dd, J=3, 9Hz, 1H), 4.81(m, 1H), 4.42(br, 2H), 4.23(m, 1H), 4.00(m, 1H), 3.35(m, 1H), 3.25(m, 1H), 2.62(m, 2H), 2.40(s, 3H), 1.61 (m, 2H), 1.37 (m, 2H), 0.91 (t, J=7.3Hz, 3H); ¹⁹ F NMR (471MHz, D ₂ O) δ-78.32; MS (CI/NH ₃ ) m/e 239 (M+H) ⁺ ; _Anal . Calcd. for _{C20H27N2O4FS :} C, 58.52; H, 6.63 _; N, 6.82; Found: C, 58.23; H, 6.68;

Example 103

6-Fluoro-3-(1-(2-methylpropyl)-2-(R)-azetidinylmethoxy)pyridine p-toluenesulfonate

According to the method of Example 98c, but using the starting material isobutyraldehyde instead of paraformaldehyde, the title compound was prepared in 43% yield: mp103-104°C; ¹ H NMR (500MHz, D ₂ O) δ7.91 (br, 1H), 7.69(d, J=8.6Hz, 2H), 7.66(m, 1H), 7.37(d, J=7.9Hz, 2H), 7.11(dd, J=3, 9Hz, 1H), 4.86(m, 1H) , 4.44(br, 2H), 4.26(m, 1H), 4.04(m, 1H), 3.30(m, 1H), 3.07(dd, J=9.2, 12.8Hz, 1H), 2.62(m, 2H), 2.40(s, 3H), 2.04(m, 1H), 0.98(d, J=7.3Hz, 3H), 0.96(d, J=7.3Hz, 3H); ¹⁹ FNMR (471MHz, D ₂ O) δ-78.3 ; MS (DCI/NH ₃ ) m/e 239 (M+H) ⁺ ; Anal. Calcd. for C ₂₀ H ₂₇ N ₂ O ₄ FS: C, 58.52; H, 6.63; N, 6.82; Found: C, 58.36; H, 6.58; N, 6.77.

Example 104

6-Fluoro-3-(1-pentyl)-2-(R)-azetidinylmethoxy)pyridine p-toluenesulfonate

According to the method of Example 472c, but using valeraldehyde instead of paraformaldehyde, the title compound was prepared in 64% yield: mp77-79°C; ¹ H NMR (500MHz, D ₂ O) δ7.90 (br, 1H), 7.69 (d, J=7.9Hz, 2H), 7.65(m, 1H), 7.37(d, J=8.6Hz, 2H), 7.11(dd, J=2, 6, 8.5Hz, 1H), 4.82(m, 1H), 4.42(br s, 2H), 4.23(m, 1H), 4.01(m, 1H), 3.35(m, 1H), 3.23(m, 1H), 2.62(q, J=8.5Hz, 2H) , 2.40(s, 3H), 1.62(m, 2H), 1.31(m, 4H), 0.86(m, 3H); ¹⁹ F NMR (471MHz, D ₂ O) δ-78.3; MS(CI/NH ₃ ) m/e 253 (M+H) ⁺ ; Anal. Calcd. _{for C21H29N2O4FS :} C, 59.41; H _, 6.89; N, 6.60; Found: C, 59.25; 6.48.

Example 105

6-Fluoro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine p-toluenesulfonate

105a.6-fluoro-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine

The procedure of Example 98 was followed, but substituting 1-Cbz-2-(S)-azetidinemethanol for 1-Cbz-2-(R)-azetidinylmethanol. The product was obtained as a clear oil: ¹ H NMR (dmso-d ₆ , 300 MHz) δ 2.21 (m, 1H), 2.38 (m, 1H), 3.87 (t, J=7Hz, 2H), 4.19 (dd, J= 4, 11Hz, 1H), 4.34(dd, J=4, 11Hz, 1H), 4.54(m, 1H), 5.01(m, 2H), 6.97(dd, J=3, 9Hz, 1H), 7.28(m , 5H), 7.50 (m, 1H), 7.85 (m, 1H); MS (CI/NH ₃ ) m/e 317 (M+H) ⁺ ; Anal. Calcd. for C ₁₇ H ₁₇ FNO ₃ : C, 64.55 ; H, 5.42; N, 8.86; Found: C, 64.37; H, 5.30; N, 8.83. [α] _D -74.7 (c1.0, chloroform).

105b. 6-Fluoro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine p-toluenesulfonate

The title compound was prepared as in Example 98c, substituting 6-fluoro-3-(1-Cbz-2-(S)-azetidinyl)pyridine for its R enantiomer. The product was obtained as a white solid: mp 124-126°C; [α] _D =+15.93 (c0.5, MeOH). ¹ H NMR (300MHz, D ₂ O) δ7.92(s, 1H), 7.68(m, 3H), 7.38(d, 2H, J=8.0Hz), 7.11(dd, 1H, J=2.5, 8.5 Hz ), 4.8(br s, 1H), 4.45(m, 2H), 4.27(br s, 1H), 4.02(br s, 1H), 2.99(s, 3H), 2.68(m, 2H), 2.40(s , 3H); MS (CI/NH ₃ ) m/z 197 (M+H) ⁺ ; Anal. Calcd. for C ₁₀ H ₁₃ FN ₂ O·TsOH: C, 55.42; H, 5.75; N, 7.60; found : C, 55.33; H, 5.74; N, 7.59.

Example 106

6-Fluoro-3-(1-ethyl)-2-(S)-azetidinylmethoxy)pyridine p-toluenesulfonate

The title compound was prepared according to the method of Example 105b, but the starting material acetaldehyde was used instead of paraformaldehyde, and the product was obtained as a white solid in 47% yield: mp101-103°C; ¹ HNMR (500MHz, D ₂ O) δ7.91 (m, 1H), 7.69 (d J = 8Hz, 2H), 7.66 (m, 1H), 7.37 (d, J = 8Hz, 2H), 7.11 (dd, J = 9.2Hz, 1H), 4.80 (m, 1H), 4.44(m, 2H), 4.23(m, 1H), 3.98(m, 1H), 3.42(1), 3.30(dq, J=12, 7Hz, 1H), 2.63(br q, J=8Hz , 2H), 2.40(s, 3H), 1.24(t, J=7Hz, 3H); ¹⁹ F NMR (471MHz, D ₂ O) δ-78.36; MS (CI/NH ₃ ) m/e 211 (M+ H) ⁺ ; Anal. _Calcd . for _C18H23N2O4FS : C, 56.53; H, 6.06 _{; N} , 7.32; Found: C, 56.54; H, 6.05;

Example 107

6-Fluoro-3-(1-propyl)-2-(S)-azetidinylmethoxy)pyridine p-toluenesulfonate

The title compound was prepared according to the method of Example 105b, but the paraformaldehyde was replaced by propionaldehyde, and the product was obtained as a white solid in 74% yield: mp95-104°C; ¹ H NMR (500MHz, D ₂ O) δ7.90( m, 1H), 7.68(d, J=8Hz, 2H), 7.65(m, 1H), 7.36(d, J=8Hz, 2H), 7.10(dd, J=9, 2Hz, 1H), 4.81(m , 1H), 4.41(m, 2H), 4.23(m, 1H), 4.00(q, J=10Hz, 1H), 3.34(m, 1H), 3.20(m, 1H), 2.62(m, 2H), 2.39(s, 3H), 1.65(m, 2H), 0.95(t, J=7Hz, 3H); ¹⁹ F NMR (471MHz, D ₂ O) δ-78.34; MS(CI/NH ₃ ) m/e 225 (M+1) ⁺ ; _Anal . Calcd. for _C19H25N2O4FS : C, 57.56; H, 6.36; N, 7.07 _; Found: _C , 57.51; H, 6.27;

Example 108

6-Fluoro-3-(1-butyl)-2-(S)-azetidinylmethoxy)pyridine p-toluenesulfonate

The title compound was prepared according to the method of Example 105b, but using butyraldehyde instead of paraformaldehyde to obtain the product as a white solid in 82% yield: mp88-93°C; ¹ H NMR (500MHz, D ₂ O) δ7.90( m, 1H), 7.69(d, J=8 Hz, 2H), 7.65(m, 1H), 7.37(d, J=8Hz, 2H), 7.10(dd, J=9, 2Hz, 1H), 4.81( m, 1H), 4.42(m, 2H), 4.22(m, 1H), 4.00(q, J=9Hz, 1H), 3.37(m, 1H), 3.25(m, 1H), 2.62(m, 2H) , 2.40(s, 3H), 1.61(m, 2H), 1.37(hex, J=7Hz, 2H), 0.91(t, J=7Hz, 3H); ¹⁹ FNMR (471MHz, D ₂ O) δ-78.31; MS (CI/NH ₃ ) m/e 239 (M+H) ⁺ ; Anal. Calcd. for C ₂₀ H ₂₇ N ₂ O ₄ FS: C, 58.52; H, 6.63; N, 6.82; Found: C, 58.28 ; H, 6.64; N, 6.60.

Example 109

6-Fluoro-3-(1-(2-methylpropyl)-2-(S)-azetidinylmethoxy)pyridine p-toluenesulfonate

The title compound was prepared according to the method of Example 105b, but using isobutyraldehyde instead of paraformaldehyde to obtain the product as a white solid in 83% yield: mp 104-106°C; ¹ H NMR (500 MHz, D ₂ O) δ 7.91 ( m, 1H), 7.70(d, J=8Hz, 2H), 7.66(m, 1H), 7.37(d, J=8Hz, 2H), 7.11(dd, J=9, 2Hz, 1H), 4.86(m , 1H), 4.45(m, 2H), 4.25(m, 1H), 4.05(m, 1H), 3.29(m, 1H), 3.07(dd, J=13, 9Hz, 1H), 2.62(m, 2H ), 2.40(s, 3H), 2.05(m, 1H), 0.97(t, J=7Hz, 6H); ¹⁹ F NMR (471MHz, D ₂ O) δ-78.29; MS(CI/NH ₃ )m/ ^Anal . _{Calcd. for C20H27N2O4FS :} C, 58.52; H, _6.63 ; N, 6.82; Found: C, 58.36; _H , 6.68; N, 6.73.

Example 110

6-Fluoro-3-(1-pentyl-2-(S)-azetidinylmethoxy)pyridine p-toluenesulfonate

The title compound was prepared according to the method of Example 105b, but valeraldehyde was used instead of paraformaldehyde to obtain the product as a white solid in 49% yield: mp 71-73°C; ¹ H NMR (500 MHz, D ₂ O) δ 7.91 (m , 1H), 7.69(d, J=8Hz, 2H), 7.66(m, 1H), 7.37(d, J=8Hz, 2H), 7.11(m, 1H), 4.82(m, 1H), 4.43(m , 2H), 4.23(m, 1H), 3.99(m, 1H), 3.36(m, 1H), 3.24(m, 1H), 2.62(m, 2H), 2.40(s, 3), 1.63(m, 2H), 1.32 (m, 4H), 0.87 (m, 3); ¹⁹ F NMR (471 MHz, D ₂ O) δ-78.31; MS (DCI/NH ₃ ) m/e253 ((M+H) ⁺ ); _{Anal. Calcd} . for _C21H29N2O4FS : C, 59.41; H, 6.89; N, _6.60 ; Found: C, 59.13; H, 6.86; N, 6.53.

Example 111

6-Fluoro-3-(1-(1,1-dimethylpropyl)-2-(R)-azetidinylmethoxy)pyridine p-toluenesulfonate

111a.5-[1-(1,1-Dimethyl-2-propynyl)-(2S)-azetidinylmethoxy]-2-fluoro-pyridine

Add 5-((2S)-azetidinylmethoxy]-2-fluoropyridine (530 mg, 2.91 mmol) and 3-chloro-3-methyl-1-butyne ( To a solution of 0.654ml, 5.82mmol) in THF (6ml) was added a catalytic amount of copper(I) iodide (14mg, 0.15mmol), causing a precipitate to form. The mixture was stirred for 1 hour, diluted with ether and washed with 1N aqueous hydrochloric acid. The layers were separated, the aqueous phase was basified with 15% aqueous sodium hydroxide (PH=12) and extracted with dichloromethane. The dichloromethane extract was dried over sodium sulfate and concentrated. After chromatography (silica gel, 98:2 dichloromethane /methanol) to obtain 290 mg (40%) of the title compound as a pale yellow oil: [α] _D ²³ -93.8 (c1.03, dichloromethane); ¹ H NMR (CDCl ₃ ,) δ1.21 (s, 3H), 1.29(s, 3H), 2.02(m, 1H), 2.14(m, 1H), 2.39(s, 1H), 3.23-3.29(m, 2H), 3.90-4.06(m, 3H), 3.90 -4.06(m, 3H), 6.85(dd, J=1.7, 8.8Hz, 1H), 7.32(m, 1H), 7.82(dd, J=1.7, 3.1Hz, 1H); MS(CI/NH ₃ ) m/z: 249 (M+H ⁺ ).

111b.5-[1-(1,1-Dimethyl-2-propynyl)-(2S)-azetidinylmethoxy]-2-fluoro-pyridine p-toluenesulfonate

To 5-[1-(1,1-dimethyl-2-propynyl)-(2S)-azetidinylmethoxy]-2-fluoropyridine (58 mg , 0.23mmol) in ethanol (3ml) was added p-toluenesulfonic acid monohydrate (44mg, 0.23mml). The solution was stirred for 1 hour, then the solvent was evaporated in vacuo. The solid was triturated with ether and dried in vacuo to afford 93 mg (95%) of the title compound as a white solid: mp 155-157°C; ¹ H NMR (D ₂ O) δ 1.55(s, 3H), 1.62(s, 3H ), 2.40(s, 3H), 2.55(m, 2H), 3.26(s, 1H), 4.06(m, 1H), 4.21(m, 1H), 4.42(d, J=4.0Hz, 2H), 5.05 (m, 1H), 7.10(dd, J=2.6, 8.8Hz, 1H), 7.38(d, J=8.1Hz, 2H), 7.67(m, 1H), 7.70(d, J=8.5Hz, 2H) , 7.91 (m, 1H); MS (CI/NH ₃ ) m/z: 249 (M+H ⁺ ). _{Anal. Calcd} . for _C14H17FN2O - _C7H8O3S : C, 59.98; H, 5.99; _{N ,} 6.66; Found: C, 59.78; H, 5.91; N, 6.52.

111c.5-[1-(1,1-Dimethylpropyl)-(2S)-azetidinylmethoxy]-2-fluoropyridine

Under hydrogen (balloon), 5-[1-(1,1-Dimethyl-2-propynyl)-(2S)-azetidinylmethoxy]- A suspension of 2-fluoropyridine (210mg, 0.846mmol) and 10% palladium on charcoal (20mg) in methanol (10ml) was stirred for 18 hours. The catalyst was removed by filtration through a pad of celite (methylene chloride wash) and the organic solution was concentrated to give 206 mg of a yellow oil. Purification by chromatography (silica gel, 90:10 dichloromethane/methanol) afforded 190 mg (89%) of the title compound as a colorless oil: [α] _D ²³ -40.9 (c1.13, dichloromethane); ¹ H NMR (CDCl ₃ ) δ0.84(t, J=7.1Hz, 3H), 0.92(s, 3H), 0.94(s, 3H), 1.30(q, J=7.1Hz, 2H), 1.95(m, 1H ), 2.07(m, 1H), 3.10-3.35(m, 2H), 3.82(m, 1H), 3.92-4.05(m, 2H), 6.84(m, 1H), 7.31(m, 1H), 7.81( dd, J=2.4, 2.9 Hz, 1H); MS (CI/ _NH3 ) m/z: 253 (M+H ⁺ ).

111d.5-[1-(1,1-Dimethylpropyl)-2-(S)-azetidinylmethoxy]-2-fluoropyridine p-toluenesulfonate

The free amine from step 111c above (84mg, 0.33mmol) was dissolved in ethanol (3ml) and p-toluenesulfonic acid monohydrate (63mg, 0.33mmol) was added. The solution was stirred for 2 hours, then the volatiles were removed in vacuo. The solid was triturated with ether and dried under high vacuum to give 145 mg (95%) of the title compound as a white solid: mp 84-86 °C; ¹ H NMR (D ₂ O) δ 0.95 (t, J = 7.3 Hz, 3H ), 1.31(s, 3H), 1.37(s, 3H), 1.68(m, 2H), 2.40(s, 3H), 2.54(t, J=8.6Hz, 1H), 4.02(m, 1H), 4.15 (m, 1H), 4.43(m, 2H), 4.97(m, 1H), 7.11(dd, J=2.4, 9.2Hz, 1H), 7.38(d, J=7.9Hz, 2H), 7.67(m, 1H), 7.70 (d, J=8.6Hz, 2H), 7.91 (dd, J=1.2, 3.1Hz, 1H); MS (CI/ _NH3 ) m/z: 253 (M+H ⁺ ). _Anal. Calcd. for _{C14H17FN2O - 1.2C7H8O3S} : C, 58.62; H, 6.72; _N , _6.10 ; Found: C, 58.62; H, 6.81; N, 6.45.

Example 112

6-Fluoro-3-(1-(1,1-dimethylpropyl)-2-(R)-azetidinylmethoxy)pyridine p-toluenesulfonate

Following the procedure of Examples 111a and b, but substituting 5-(2R)-azetidinylmethoxy)-2-fluoropyridine for 5-(2S)-azetidinylmethoxy )-2-fluoropyridine, preparation of 5-[1-(1,1-dimethyl-2-propynyl)-(2S)-azetidinylmethoxy]-2-fluoropyridine , yield 21%. Following the procedure of Examples 111c and d, but using the enantiomeric starting material 5-[1-(1,1-dimethyl-2-propynyl)-(2R)-azetidinylmethoxy] -2-fluoropyridine instead of its 5-[1-(1,1-dimethyl-2-propynyl)-(2S)-azetidinylmethoxy]-2-fluoropyridine, Title compound prepared as a white solid: mp 67-70°C; ¹ H NMR (D ₂ O) δ 0.95 (t, J = 7.3 Hz, 3H), 1.31 (s, 3H), 1.37 (s, 3H), 1.67(m, 2H), 2.40(s, 3H), 2.54(t, J=8.5Hz, 1H), 4.02(m, 1H), 4.15(m, 1H), 4.43(m, 2H), 4.96(m , 1H), 7.11(dd, J=3.0, 9.2Hz, 1H), 7.38(d, J=8.5Hz, 2H), 7.67(m, 1H), 7.70(d, J=7.9Hz, 2H), 7.92 (dd, J=1.8, 3.1 Hz, 1H); MS (CI/ _NH3 ) m/z: 253 (M+H ⁺ ). _Anal. Calcd. for _{C14H17FN2O.C7H8O3S.0.8H2O} : C, _{57.46 ;} H, _7.03 ; N _{, 6.38} ; Found: C, 57.46; H, 6.95; N, 6.27.

Example 113

6-Difluoromethyl-3-((1-methyl-2-(S)-azetidinyl)methoxy)pyridine citrate

113a.6-Hydroxymethyl-3-((1-tert-butoxycarbonyl-2-(S)-azetidinyl)methoxy)pyridine

According to the method of Example 2a, a sample (1.64g, 8.18mml) of (S)-1-tert-butoxycarbonyl-2-azetidinemethanol and 1.05g (6.29mmol) of 6-acetoxy Methyl-3-hydroxypyridine (prepared as described by Deady and Dayhe, Aust. J. Chem., 2565: 36 (1983)) with triphenylphosphine (540 mg, 2.06 mmol) and DEAD (0.33 ml, 2.06 mmol) THF (25ml) solution was reacted. The product in methanol (4ml) containing potassium hydroxide (450mg) was stirred at room temperature for 4 hours, then neutralized and concentrated. The residue was purified by chromatography (silica gel, 1:1 ethyl acetate:hexanes) to afford the title compound (240 mg, 41% for two steps). MS (DCI/NH ₃ ) m/e: 295 (M+H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ1.42 (s, 9H), 2.24-2.48 (m, 2H), 3.84-3.96 ( m, 2H), 4.18(dd, J=2.6, 11Hz, 1H), 4.40(m, 1H), 4.53(m, 1H), 4.82(s, 2H), 7.36(d, J=8.5Hz, 1H) , 7.51 (m, 1H), 8.31 (d, J=3.0Hz, 1H).

113b.6-Difluoromethyl-3-((1-tert-butoxycarbonyl-2-(S)-azetidinyl)methoxy)pyridine

To a sample of the compound from Step 113a above (127mg, 0.43mmol) in phosphoric acid (3ml) was added dicyclohexylcarbodiimide (310mg, 1.5mml) and the solution was stirred at 25°C for 2 hours. The solid was filtered, and the filtrate was washed with saturated sodium bicarbonate. The organic layer was dried (magnesium sulfate), filtered and the solvent was removed. The residue (110 mg) was used in the next reaction without further purification. MS (DCI/NH ₃ ) m/e: 293 (M+H) ⁺ ; To a solution of the crude product (110 mg, 0.38 mmol) in dichloromethane (3 ml) was added triethylamine (0.1 ml), and the solution Cool to -780°C. To this solution was added DAST (42 µl, 0.39 mmol), and the solution was stirred at -78-0°C for 1.5 hours. The reaction mixture was allowed to warm to room temperature and quenched by the addition of saturated sodium bicarbonate. The mixture was extracted with chloroform, the solvent was removed, and the residue was chromatographed (silica gel, ethyl acetate/hexane, 1:1) to give the title compound (52 mg, 44%): MS (DCI/NH ₃ ) m/e: 315 (M+H) ⁺ ; ¹ HNMR (CDCl ₃ 300MHz) δ1.55(s, 9H), 2.34(s, 3H), 2.11-2.44(m, 2H), 3.90(t, J=7.8Hz, 2H) , 4.17(dd, J=2.9, 10Hz, 1H), 4.36(m, 1H), 4.53(m, 1H), 6.62(t, J=55.5Hz, 1H), 7.36(dd, J=2.5, 8.6Hz ), 7.57 (d, J=8.5Hz, 1H), 8.36 (d, J=3.0H, 1H).

113c.6-Difluoromethyl-3-((1-methyl-2-(S)-azetidinyl)methoxy)pyridine citrate

The compound from Step 113b above was treated with p-toluenesulfonic acid (64.6 mg, 0.34 mmol) in dichloromethane (3 ml). The resulting compound was refluxed for 6 hours. The solvent was removed under reduced pressure. The residue was triturated several times with ether to give a very hygroscopic white solid (102 mg). MS(CI/NH ₃ ) m/e: 215(M+H) ⁺ , 232(M+NH ₄ ) ⁺ ; ¹ H NMR (CDCl ₃ 300MHz) δ2.38(s, 3H), 2.69(q, J =8.5Hz, 2H), 4.03-4.11(m, 2H), 4.45(d, J=4.4Hz, 2H), 4.96(m, 1H), 6.79(t, J=55.5Hz, 1H), 7.35(d , J=7.5Hz, 2H), 7.60(dd, J=2.7, 8.5Hz, 1H), 7.68(d, J=8.2Hz, 2H), 7.72(d, J=8.8Hz, 1H), 8.39(d , J=3.0Hz, 1H). _Anal. Calcd. for _{C10H12F2N2O 2.5C7H8SO3 2H2O :} C _{, 48.52} ; H, 5.33; N, _4.12 ; Found: C, 48.46; H, 5.27; N , 4.10. [α] _D ²⁵ =1° (c0.28, methanol).

Example 114

3-(2-(R)-Azetidinylmethoxy)-5-chloropyridine p-toluenesulfonate

114a. 3-(1-tert-butoxycarbonyl-2-(R)-azetidinylmethoxy)-5-chloropyridine p-toluenesulfonate

Potassium hydroxide (0.2 g, 3.8 mmol) was added to a solution of 5-chloro-3-hydroxypyridine (0.3 g, 2.6 mmol) in DMF at room temperature. Then 1-tert-butoxycarbonyl-2-(R)-azetidinemethyl-p-toluenesulfonate (0.8 g, 2.4 mmol, from Example 10d) was added and the reaction mixture was stirred at 80 °C for 16 hours . DMF was removed by washing with water/brine (1:1) in ethyl acetate. The organic layer was dried, concentrated and chromatographed (silica gel, hexane/ethyl acetate, 5:1-1:1) to give an oil (0.6 g, 87%). ¹ H NMR (CDCl ₃ , 300MHz) δ1.43(s, 9H), 2.21-2.40(m, 2H), 3.89(t, 2H, J=8Hz), 4.12(m, 1H), 4.36(m, 1H ), 4.52(m, 1H), 7.29(m, 1H), 8.20(d, 1H, J=2Hz), 8.25(d, 1H, J=3Hz); MS(CI/NH ₃ ) m/z: 299 (M+H) ⁺ ;

114b. 3-(2-(R)-Azetidinylmethoxy)-5-chloropyridine p-toluenesulfonate

To 3-(1-tert-butoxycarbonyl 2-(R)-azetidinylmethoxy)-5-chloropyridine (0.6 g, 2.1 mmol) solution was added TFA (3 ml). The reaction mixture was stirred at 0°C-25°C. After 30 minutes, it was basified with 15% sodium hydroxide and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, concentrated and chromatographed (silica gel, dichloromethane/methanol, 10:0.4-10:1) to give an oil (0.4 g, 93%): ¹ H NMR (CDCl ₃ , 300 MHz) δ2. 44-2.64(m, 2H), 3.80(m, 1H), 3.98(m, 1H), 4.08(m, 1H), 4.24(m, 1H), 4.61(m, 1H), 7.26(m, 1H) , 8.23 (m, 1H); MS (CI/NH ₃ ) m/z: 199 (M+H ⁺ ). The free base was converted to a salt with TsOH, white solid: mp 100-102°C; ¹ H NMR (D ₂ O, 300 MHz) δ 2.38 (s, 3H), 2.60-2.78 (m, 2H), 4.00-4.20 (m, 2H), 4.39-4.43(m, 2H), 4.98(m, 1H), 7.36(d, 2H, J=8Hz), 7.60(m, 1H), 7.67(d, 2H, J=8Hz) , 8.20-8.24 (m, 2H); MS (CI/NH ₃ ) m/z: 199 (M+H) ⁺ . _Anal. Calcd. _{for C9H11ClN2O.TsOH.0.5H2O} : C, 50.59; H, 5.31; N, _7.37 ; Found: C, 50.91; H, 5.02; N, 7.00. [α] _D ²⁵ 9.3° (c0.4, methanol).

Example 115

6-Methyl-3-(2-(R)-azetidinylmethoxy)pyridine

The title compound was prepared according to the method of Example 17, but substituting 1-tert-butoxycarbonyl-2-(R)-azetidinemethanol for the (S) enantiomer and substituting 6-methyl-3- Pyridinol instead of 3-bromo-2-chloro-5-hydroxypyridine. After deprotection and conversion to the hydrochloride salt as in Example 17a, a white solid was obtained: mp 134-136 °C; ¹ H NMR (D ₂ O 300 MHz) δ 2.48 (s, 3H), 2.69 (m, 2H), 4.12(m, 2H), 4.41(d, J=4Hz, 2H), 4.95(septet, J=4Hz, 1H), 7.32(d, J=9Hz, 1H), 7.47(dd, J=3, 9Hz , 1H), 8.20 (d, J=3Hz, 1H); MS (DCI/NH ₃ ) m/e: 179 (M+H) ⁺ ; Calculation for C ₁₀ H ₁₄ N ₂ O·HCl·H ₂ O Values: C, 54.13; H, 7.18; N, 12.67; Found: C, 53.85; H, 6.98; N, 12.38.

Example 116

2,6-Difluoro-3-(2-(S)-azetidinylmethoxy)pyridine p-toluenesulfonate

116a. 3-Hydroxy-2,6-difluoropyridine

A 2M solution of LDA in heptane/THF/ethylbenene (38ml, 76mmol) was added to a solution of 2,6-difluoropyridine (6.7ml, 73.8mmol) in THF (100ml, cooled to -78°C). The mixture was stirred at -78°C for 1 hour and trimethyl borate (6.8ml, 89.7mmol) was added. The mixture was stirred for 1 h, allowed to warm to 20 °C, then the reaction was quenched with HOAc (10 ml). The solution was basified with 20% aqueous sodium hydroxide solution (20ml), hydrogen peroxide (50%, 200ml) was added, and the mixture was stirred for 16 hours. The mixture was neutralized by adding hydrochloric acid (2M, aq), extracted with ethyl acetate. The combined ethyl acetate extracts were dried (magnesium sulfate). The solvent was evaporated in vacuo and the crude product was chromatographed (silica gel, hexane/ethyl acetate 9:1-6:4) to yield 2.7 g (28%) of the title compound. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ6.75 (dd, J=3.0, 5.5 Hz, 1H), 7.48 (m, 1H). MS (DCI/NH ₃ ) m/e: 149 (M+NH ₄ ) ⁺ .

116b.2,6-Difluoro-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine

2,6-Difluoro-3-hydroxypyridine (2 g, 15.26 mmol), 1-Cbz-2-(S)-azetidinylmethyl-p-toluenesulfonate (5.73 g, 15.26mmol, prepared in Example 105) and potassium hydroxide (1.4g, 24.9mmol) were mixed in DMF (15ml), heated at 90°C for 1 hour, cooled to 20°C and poured into brine (100ml) . The resulting mixture was extracted with ether. The combined ether extracts were washed with 50% brine and dried (magnesium sulfate). The solvent was evaporated in vacuo, and the crude product was chromatographed (silica gel, hexane/ethyl acetate 95:5-6:4) to obtain 1.75 g (34%) of the title compound: ¹ H NMR (DMSO-d ₆ , 120°C 300 MHz) δ2 .22(m, 1H), 2.42(m, 1H), 3.85-3.90(m, 2H), 4.23(m, 1H), 4.40(m, 1H), 4.54(m, 1H), 5.01(s, 1H ), 6.93 (dd, J=3.0, 5.5Hz, 1H), 7.29 (m, 5H), 7.77 (m, 1H); MS (DCI/NH ₃ ) m/e: 335 (M+H) ⁺ , 352 (M+NH ₄ ) ⁺ . _Anal. Calcd. _{for C17H16F2N2O3} : _C , 61.07; H, _54.82 ; N, 8.38; Found: C, 61.10; H, 4.84; N, 7.90

116c. 2,6-Difluoro-3-(2-(S)-azetidinylmethoxy)pyridine p-toluenesulfonate

2,6-Difluoro-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine (640 mg, 1.9 mmol) from Example 116b was mixed with charcoal (50 mg) 10% Pd and p-toluenesulfonic acid monohydrate (1.1 g, 5.7 mmol) were mixed in 30 ml ethanol, and the mixture was stirred under hydrogen for 16 hours. The mixture was concentrated, triturated with ether, then recrystallized from ethyl acetate/ether to give 231 mg (32.4%) of the title compound: mp 140-143°C; ¹ H NMR (D ₂ O 300 MHz) δ 2.40 (s, 3H ), 2.69(m, 2H), 4.12(m, 2H), 4.46(d, J=4.5, 2H), 4.94(m, 1H), 7.01(m, 1H), 7.38(d, J=8.0, 2H ), 7.70 (d, J=8.0, 2H), 7.81 (m, 1H); MS (DCI/NH ₃ ) m/e: 201 (M+H) ⁺ , 218 (M+NH ₄ ) ⁺ . _{Anal. Calcd. for C9H10F2N2O-C7H8O3S : C , 51.61} ; H, 4.87; N, 7.52; Found: C _, 51.37; H, 4.89; N, 7.40. [α] _D -1.44° (c1 MeOH).

Example 117

2-Fluoro-6-methyl-3-(2-(S)-azetidinylmethoxy)pyridine p-toluenesulfonate

117a. 3-Hydroxy-6-methyl-2-nitropyridine

5-Hydroxy-6-picoline (23.6g, 216mmol) was dissolved in concentrated sulfuric acid (50ml) and cooled to 0°C. Fuming nitric acid (50ml) was added over 1 hour. The solution was stirred at room temperature for 1 hour, poured into ice (400 g) and filtered. The solid was dissolved in ethyl acetate and washed with brine (100ml). The organic extracts were dried (magnesium sulfate) and the solvent was evaporated to give 12.1 g (36.3%) of the title compound. mp 102-105°C; ¹ H NMR (DMSO-d ₆ , 300MHz) δ 2.44 (s, 3H), 7.52 (d, J=8.5, 1H), 7.58 (d, J=8.5Hz, 1H); MS (ESI-Q1 MS) m/e: 153 (MH) ⁺ . _{Anal .} Calcd. for _C6H6N2O3 : C, 46.76; H, 3.92; N _, 18.18; Found: C, 46.65; H, 3.98; N, 18.10.

117b. 2-Amino-3-hydroxy-6-methylpyridine

3-Hydroxy-6-methyl-2-nitropyridine (10.5 g, 68 mmol) from Example 117a was mixed with 10% Pd/C (100 mg) in ethanol (100 ml) and the mixture was stirred under hydrogen. The mixture was 16 hours. The mixture was filtered and concentrated to give 8.40 g (99%) of the title compound: mp 141-145 °C; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 2.14 (s, 3H), 6.22 (d, J = 7.5 Hz, 1H), 6.71 (d, J=7.5Hz, 1H); MS (DCI/NH ₃ ) m/e: 125 (M+H) ⁺ , 142 (M+NH ₄ ) ⁺ .

117c.2-Fluoro-3-hydroxy-6-methylpyridine

2-Amino-3-hydroxy-6-picoline (8.35 g, 67.25 mmol) from Example 117b was dissolved in aqueous HF (48% 100 ml) and cooled to -5°C. Sodium nitrite (5.2 g, 75.4 mmol) was added at a rate to maintain the temperature below 0°C. After the addition was complete, the solution was heated to 30°C. After 30 minutes, the solution was cooled to 0° C. and neutralized by adding sodium hydroxide (20% aq). The aqueous mixture was extracted with ethyl acetate. The organic extract was dried (magnesium sulfate), the solvent was evaporated and the crude product was chromatographed (silica gel, hexane/ethyl acetate 1:1) to give 4.68 g (54.7%) of the title compound: mp 133-135°C; ¹ H NMR ( DMSO-d ₆ , 300 MHz) δ 2.29 (s, 3H), 6.98 (d, J=8Hz, 1H), 7.26 (dd, J=8Hz, 1H). MS (DCI/NH ₃ ) m/e 128 (M+H) ⁺ , 145 (M+NH ₄ ) ⁺ . _Anal. Calcd. for _C6H6FNO : C, 56.69; H, 4.76; N, 11.02; Found: C, 56.72; H, 4.73; N, 11.03.

117d.2-fluoro-6-methyl-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine

2-Fluoro-3-hydroxy-6-methylpyridine (1 g, 7.87 mmol), 1-Cbz-2-(S)-azetidinylmethyl-p-toluenesulfonic acid from Example 117c The ester (2.37g, 7.5mmol, prepared as in Example 105) and potassium hydroxide (0.66g, 11.76mmol) were mixed in DMF (25ml) and heated at 90°C for 1 hour, cooled to 20°C and poured into brine ( 100ml). The resulting mixture was extracted with ether. The combined ether extracts were washed with 50% brine and dried (magnesium sulfate). The solvent was evaporated in vacuo, and the crude product was chromatographed (silica gel, hexane/ethyl acetate 3:1) to obtain 1.31 g (53%) of the title compound: ¹ H NMR (DMSO-d ₆ , 120°C 300 MHz) δ 2.26 (m , 1H), 2.33(s, 3H), 2.48(m, 1H), 3.82-3.88(m, 2H), 4.19(q, J=3, 1H), 4.35(q, J=4.5, 1H), 4.53 (m, 1H), 5.01(s, 2H), 7.01(d, J=8, 1H), 7.28(m, 5H), 7.43(m, 1H); MS(DCI/NH ₃ ) m/e: 331 (M+H) ⁺ , 348(M+NH ₄ ) ⁺ . _Anal. Calcd. _{for C18H18FN2O3} : C, 65.44; H, 5.8; N, _8.48 ; Found: C, 65.04; H, 5.86; N, 7.90. [α] _D -70.38 (c 1 , MeOH).

117e. 2-Fluoro-6-methyl-3-(2-(S)-azetidinylmethoxy)pyridine p-toluenesulfonate

2-Fluoro-6-methyl-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine (714 mg, 2.16 mmol) from Example 117d was mixed with 10% Pd /C (50 mg) and p-toluenesulfonic acid monohydrate (830 mg, 4.36 mmol) were mixed in 30 ml of ethanol, and the mixture was stirred under hydrogen for 16 hours. The mixture was filtered, concentrated, the residue was triturated with ether, and the product was recrystallized from ethyl acetate/ether to give 480 mg (60%) of the title compound: mp 141-143°C; ¹ HNMR (D ₂ O 300 MHz) δ 2.40 ( s, 6H), 2.65-2.71(m, 2H), 4.07-4.16(m, 2H), 4.43(d, J=4.5, 2H), 4.81-95(m, 1H), 7.16(d, J=8.0 , 1H), 7.73 (d, J=8.0, 2H), 7.55 (d, J=8.0, 2.5, 2H), 7.70 (d, J=8.0, 2H). MS (DCI/NH ₃ ) m/e: 197 (M+H) ⁺ 214 (M+NH ₄ ) ⁺ . _Anal . _Calcd . for _C10H13FN2O - _C7H8O3S : C, 55.42; H _, 5.75; N, 7.60; Found: C _, 55.27; H, 5.69; N, 7.44. [α] _D -3.2 (c1 MeOH).

Example 118

2-Fluoro-6-methyl-3-(2-(R)-azetidinylmethoxy)pyridine p-toluenesulfonate

118a.2-Fluoro-6-methyl 3-(1-Cbz-2-(R)-azetidinylmethoxy)pyridine

2-Fluoro-3-hydroxy 6-picoline from Example 117c (0.5 g, 3.47 mmol), 1-Cbz-2-(R)-azetidinyl from Example 98a Methyl p-toluenesulfonate (1.1g, 3.9mmol) and potassium hydroxide (0.3g, 5.33mmol) were mixed in DMF (5ml) and heated at 80°C for 2 hours, cooled to room temperature and poured into saturated ammonium chloride (100ml). The resulting mixture was extracted with ether, and the combined ether extracts were washed with 50% brine and dried (magnesium sulfate). The solvent was evaporated in vacuo, and the crude product was chromatographed (silica gel, hexane/ethyl acetate 9:1-7:3) to obtain 592 mg (51.7%) of the title compound: ¹ H NMR (DMSO-d ₆ , 120°C 300 MHz) δ2. 22(m, 1H), 2.33(s, 3H), 2.41(m, 1H), 3.83-3.88(m, 2H), 4.19(q, J=3, 1H), 4.35(q, J=5, 1H ), 4.53(m, 1H), 5.01(s, 2H), 7.01(d, J=8, 1H), 7.28(m, 5H), 7.43(m, 1H); MS(CI/NH ₃ )m/ e: 331(M+H) ⁺ , 348(M+ _NH4 ) ⁺ . _Anal. Calcd. _{for C18H19FN2O3} : C, 65.44; H, 5.8; N, _8.48 ; Found: C, 65.19; H, 5.95; N, 8.69. [α] _D +68.15° (c1, MeOH).

118b. 2-Fluoro-6-methyl-3-(2-(R)-azetidinylmethoxy)pyridine p-toluenesulfonate

2-Fluoro-6-methyl-3-(1-Cbz-2-(R)-azetidinylmethoxy)pyridine (500 mg, 1.51 mmol) from Example 118a was mixed with 30 ml 10% Pd/C in ethanol (50 mg) and p-toluenesulfonic acid monohydrate (600 mg, 3.15 mmol) were mixed and the mixture was stirred under hydrogen for 16 hours. The mixture was filtered, concentrated, the residue was triturated with ether, and the product was recrystallized from ethyl acetate/ether to give 270 mg (50%) of the title compound: mp 158-160°C; ¹ HNMR (D ₂ O 300 MHz) δ 2.40 ( s, 6H), 2.65-2.70 (m, 2H), 4.07-4.18 (m, 2H), 4.42 (d, J=4.5, 2H), 4.91-95 (m, 1H), 7.15 (d, J=8.0 , 1H), 7.73 (d, J=8.0, 2H), 7.55 (d, J=8.0, 2.0, 2H), 7.69 (d, J=8.5, 2H). MS (DCI/NH ₃ ) m/e: 197 (M+H) ⁺ 214 (M+NH ₄ ) ⁺ . _Anal. Calcd. for _C10H13FN2O · _C7H8O3S · _0.4H2O : C _{, 54.36} ; H, 5.85; N, _7.46 ; Found: C, 54.48; H, 5.81; N, 7.28. [α] _D +2.05 (c1 MeOH).

Example 119

6-Methoxy-3-(2-(R)-azetidinylmethoxy)pyridine

119a. 5-Acetoxy-2-methoxypyridine

Under nitrogen, 24 g (193 mmol, Aldrich) of 5-amino-2-methoxypyridine dissolved in 100 ml of dimethoxyethane was added to a solution of 47.6 ml of boron trifluoride etherate cooled to -10°C middle. Tert-butyl nitrite (20.2 ml, 193 mmol, Aldrich) was added at a rate to maintain the temperature below 0°C. After standing at -10°C for 1 hour, pentane (400ml) was added to the reaction mixture, the pentane solution was discarded, the residue was washed with cold ether and dissolved in 200ml of acetic anhydride, and the resulting solution was heated to 100°C ±5°C for 1 hour. The solvent was removed in vacuo, the residue was suspended in saturated aqueous sodium carbonate (200ml) and extracted with ether (3 x 200ml). The ether solution was dried (magnesium sulfate), the solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with 95:5-80:20 hexane:ethyl acetate to afford 7.3 g (20.7%) of the title compound: MS (CI/ NH ₃ ) m/e: 168(M+H)+, 185(M+NH ₄ +)+; ¹ H NMR (CDCl ₃ 300MHz) δ2.30(s, 3H), 3.92(s, 3H), 6.75 (d, J=9.0 Hz 1H), 7.35 (dd, J=2.5, 9.0, 1H) 7.95 (d, J=3.0 Hz 1H). _Anal. Calcd. _{for C8H9NO3} : C, 57.48; H, 5.43; N, 8.38; Found: C, 57.46; H, 5.40; N, 7.99.

119b. 2-Methoxy-5-hydroxypyridine

The product of Example 119a (6.8 g, 40.7 mmol) was dissolved in 20% aqueous sodium hydroxide solution (50 mL) at 0°C, and the solution was allowed to warm to room temperature and stirred for 3 hours. The solution was neutralized by addition of hydrochloric acid, the aqueous mixture was extracted with ethyl acetate, the organic extracts were washed with water and brine, then dried (magnesium sulfate) and the solvent was evaporated to give 5.05 g (99%). The product was recrystallized from ethyl acetate/ether to give 3.6 g (70.6%) of the title compound: mp 80-82°C; MS m/e: 126 (M+H) ⁺ 143 (M+NH ₄ ) ⁺ . ¹ H NMR (CDCl ₃ 300MHz) δ3.88(s, 3H), 6.69(d, 1H, J=9.0Hz), 7.23(dd, 1H, J=3.0, 9.01H), 7.88(d, 1H, J = 3.0Hz). _Anal . Calcd. for _C6H7NO : C, 57.59; H, 5.64; N, 11.19; Found: C, 57.55; H, 5.62;

119c.6-Methoxy-3-(1-Cbz-2-(R)-azetidinylmethoxy)pyridine

3-Hydroxy-6-methoxypyridine (514 mg, 4.1 mmol) from Example 119b, 1-Cbz-2-(R)-azetidinemethyl-p-toluenesulfonate from Example 98a Ester (1.2g, 3.26mmol) and potassium hydroxide (355mg, 6mmol) were mixed in DMF (10ml) and heated at 80°C for 3 hours, cooled to room temperature and poured into sodium carbonate (100ml). The resulting mixture was extracted with ether, and the combined ether extracts were washed with 50% brine and dried (magnesium sulfate). The solvent was evaporated in vacuo, and the crude product was chromatographed (silica gel, hexane/ethyl acetate 9:1-7:3) to obtain 672 mg (67.2%) of the title compound: ¹ H NMR (DMSO-d ₆ , 120°C 300 MHz) δ2. 20(m, 1H), 2.37(m, 1H), 2.82(s, 3H), 3.82-3.88(m, 2H), 4.13(m, 1H), 4.27(m, 1H), 4.52(m, 1H) , 5.02 (s, 1H), 6.67 (d, J=11, 1H), 7.26-7.32 (m, 6H), 7.83 (d, J=3, 1H). MS (DCI/NH ₃ ) m/e: 331 (M+H) ⁺ , 348 (M+NH ₄ ) ⁺ . _Anal . Calcd. for _C18H20N2O4 : C, 65.84; H, 6.14; _N , _8.53 ; Found: C, 65.98; H, 6.23; N, 8.51.

119d.6-Methoxy-3-(2-(R)-azetidinylmethoxy)pyridine

6-Methoxy-3-(1-Cbz-2-(R)-azetidinylmethoxy)pyridine (300 mg, 0.91 mmol) from Example 119c was mixed with 10 %Pd/C (50 mg) was combined and the mixture was stirred under hydrogen for 16 hours. The mixture was filtered and concentrated. The crude free base was converted to the salt by treatment with p-toluenesulfonic acid in ethyl acetate. The mixture was concentrated, the residue was triturated with ether, and the product was recrystallized from ethyl acetate/ether to give 167 mg (33.9%) of the title compound: mp 139-142°C; ¹ H NMR (D ₂ O 300 MHz) δ 2.39 (s , 6H), 2.60-2.70(m, 2H), 2.98(s, 3H), 4.04-4.15(m, 2H), 4.36(d, J=4.5, 2H), 4.95(m, 1H), 7.08(d , J = 9.0, 1H), 7.36 (d, J = 8.0, 2H), 7.68 (d, J = 8.0, 4H), 7.75 (dd, J = 3.5, 9.5, 1H), 7.91 (d, J = 3.0 , 1H); MS (DCI/NH ₃ ) m/e: 195 (M+H) ⁺ . _{Anal .} Calcd. for _{C10H14N2O2-2C7H8O3S} : C, 53.52; H, 5.61 _; N, _5.20 ; Found: C _, 53.24; _H , 5.68; N, 5.07. [α] _D +3.55 (c1, MeOH).

Example 120

5-Ethoxy-3-(2-(S)-azetidinylmethoxy)pyridine p-toluenesulfonate

120a. 3-Benzyloxy-5-bromopyridine

Sodium hydride (60% in mineral oil) (40.9 g, 1.03 mol) in 800 ml DMF was cooled to 0°C and benzyl alcohol (105 ml, 1.02 mol) was added slowly. The reaction mixture was stirred at 20°C for 1 hour, then 3,5-dibromopyridine (200.4 g, 846 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated ammonium chloride (500ml), diluted with 400ml of water and extracted with ether. The combined ether extracts were washed with 50% brine and dried (magnesium sulfate). The solvent was evaporated in vacuo, and the crude product was recrystallized from diethyl ether to give 161 g (72%) of the title compound: mp 63-68°C; ¹ H NMR (CDCl ₃ , 300 MHz) δ 5.1 (s, 1H), 7.35-7.50 (m, 6H), 8.27-8.37 (m, 2H); MS (CI/NH ₃ ) m/z: 264, 266 (M+H) ⁺ .

120b.3-Amino-5-benzyloxypyridine

The product of step 120a (41.3 g, 156 mmol), copper(I) bromide (22.43 g, 156 mmol), methanol (275 ml) and liquid ammonia (50 ml) were mixed in a stainless steel reactor and heated to 130° C. for 24 hours . The mixture was allowed to cool to room temperature, then concentrated. The residue was suspended in 300 ml saturated aqueous sodium carbonate and extracted with dichloromethane. The combined dichloromethane solutions were washed with brine, dried (magnesium sulfate), and concentrated. The crude product was chromatographed (silica gel; hexane/ethyl acetate, 9:1-7:3) to give the title compound (15.6 g, 50%): ¹ H NMR (CDCl ₃ , 300 MHz) δ5.10 (s, 2H ), 7.30-7.45 (m, 6H), 8.20-8.30 (m, 2H); MS (CI/NH ₃ ) m/z: 201 (M+H) ⁺ .

120c.3-Acetoxy-5-benzyloxypyridine

Under nitrogen, the product from step 120b (10 g, 50 mmol) dissolved in DMF (100 ml) was added to a solution of boron trifluoride etherate (9.3 ml, 75 mmol) cooled to -15 °C to maintain the temperature below Tert-butyl nitrite (7.8ml, 65mmol) was added at a rate of -5°C. After 10 minutes at -10°C the reaction was warmed to 5°C and stirred for 30 minutes. Pentane (200ml) was added to the reaction mixture and the solid was collected by suction filtration, washed with cold diethyl ether and dissolved in acetic anhydride (150ml). The resulting solution was heated to 70°C until nitrogen evolution ceased. The solvent was removed in vacuo, the residue was suspended in saturated aqueous sodium carbonate (150ml) and extracted with ether. The ethereal extracts were dried (sodium sulfate) and concentrated. The crude product was chromatographed (silica gel, hexane/ethyl acetate, 6:1) to obtain 2.0 g of the title compound: ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.35 (s, 3H), 5.15 (s, 2H), 7.15(t, 1H, J=3Hz), 7.35-7.42(m, 5H), 8.15(d, 1H, J=3Hz), 8.30(d, 1H, J=3Hz); MS(CI/NH ₃ )m /z: 244(M+H) ⁺ , 261(M+NH ₄ ) ⁺

120d.3-Benzyloxy-5-hydroxypyridine

The product from step 120c (2g, 8.4mmol) was dissolved in methanol (15ml) and potassium carbonate (600mg, 4.34mmol) was added. When all starting material was consumed, the solution was neutralized by addition of 1N hydrochloric acid. The mixture was extracted with ether, and the organic extracts were dried (sodium sulfate) and concentrated. Trituration of the crude product with hexanes afforded the title compound (1.3 g, 82%) as a white solid: ¹ H NMR (DMSO, 300 MHz) δ 5.15 (s, 2H), 6.80 (t, 1 H, J = 3 Hz), 7.35 -7.42(m, 5H), 7.75(d, 1H, J=3Hz), 7.85(d, 1H, J=3Hz), 9.95(br s, 1H); MS(CI/NH ₃ ) m/z: 202 (M+H) ⁺ , 219(M+NH ₄ ) ⁺ .

120e.5-Benzyloxy-3-(1-Boc-2-(S)-azetidinylmethoxy)pyridine

1-Boc-2-(S)-azetidinylmethanol (36.5 g, 0.195 mol) was dissolved in 195 ml of dichloromethane, followed by addition of triethylamine (36.5 ml, 0.255 mol) and p-toluenesulfonyl chloride (48.5 g, 0.254 mol). The resulting mixture was stirred at room temperature for 16 hours. 10% sodium hydroxide solution was added rapidly and the mixture was stirred for 1 hour. After separation of the phases, the aqueous phase was extracted with additional dichloromethane and the combined organic phases were washed with sodium bicarbonate solution and brine. The resulting solution was dried (magnesium sulfate), filtered, and concentrated in vacuo to afford 63.1 g of Boc-(S)-tosyloxymethylazetidine (94.8%).

A solution of 3-benzyloxy-5-hydroxypyridine (350 mg, 1.74 mmol, from step 120d) in DMF (20 ml) was then treated with triturated potassium hydroxide (154 mg, 2.74 mmol) and stirred at 80°C for 30 minutes. Boc-(S)-tosyloxymethylazetidine (585 mg, 1.74 mmol) dissolved in DMF (5 ml) was quickly added to the mixture, and the mixture was stirred at 80°C for 16 hours. The mixture was concentrated in vacuo to remove DMF, the residue was diluted with water and extracted with EtOAc. The organic extracts were combined, dried (sodium sulfate), filtered, and concentrated in vacuo to give 800 mg of crude product. This material was purified by chromatography (silica gel, hexane/EtOAc, 10:1) to afford the title compound (575 mg, 90%): ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.40 (s, 9H), 2.26-2.30 ( m, 2H), 3.90-2.94(m, 2H), 4.16(m, 1H), 4.35(m, 1H), 4.54(m, 1H), 5.10(s, 2H), 6.95(s, 1H), 7.40 -7.46 (m, 5H), 8.20 (br s, 2H). MS (CI/NH ₃ ) m/z: 371 (M+H) ⁺ ;

120f.5-Hydroxy-3-(1-Boc-2-(S)-azetidinylmethoxy)pyridine

The product of Example 120e (5.0 g, 13.51 mmol) in methanol (25 ml) was stirred under hydrogen in the presence of 10% Pd/C (200 mg) for 4 hours, the mixture was filtered and concentrated to give 3.4 g (92%) The title compound as a colorless oil: ¹ H NMR (CDCl3., 300 Hz) δ 1.40 (s, 9H), 2.30 (m, 2H), 3.90 (t, J=9Hz, 2H), 4.10 (m, 1H) ), 4.30(m, 1H), 4.50(m, 1H), 6.85(m, 1H), 7.85(m, 1H), 7.95(m, 1H). MS (CI/ _NH3 ) 281 (M+H) ⁺ .

120g.5-ethoxy-3-(1-Boc-2-(S)-azetidinylmethoxy)pyridine

5-Hydroxy-3-(1-Boc-2-(S)-azetidinylmethoxy)pyridine (500 mg, 1.78 mmol, obtained from A solution of step 120f) in methylformamide (15ml) was stirred at room temperature for 30 minutes. Ethyl p-toluenesulfonate (430 mg, 2.14 mmol) was quickly added to the mixture, and the resultant was stirred overnight at 80°C. The mixture was concentrated to remove dimethylformamide, the residue was diluted with water and extracted with EtOAc. The organic extracts were combined, dried (magnesium sulfate), filtered and concentrated in vacuo to afford 1.0 g of unpurified product. This material was purified by flash chromatography (silica gel, hexane/ethyl acetate, 1:1) to afford 537 mg (98%) of the title compound. ¹ H NMR (CDCl ₃ , 300MHz) δ1.40(s, 9H), 1.42(t, J=6Hz, 1H), 2.30(m, 2H), 3.92(t, J=9Hz, 2H), 4.05(q , J=6Hz, 2H), 4.16(m, 1H), 4.30(m, 1H), 4.54(m, 1H), 6.80(m, 1H), 7.95(m, 2H); MS(CI/NH ₃ ) m/e: 309 (M+H) ⁺ .

120h.5-Ethoxy-3-(2-(S)-azetidinylmethoxy)pyridine

To 5-ethoxy-3-(2-(1-Boc-2-(S)-azetidinylmethoxy)pyridine (540 mg, 1.75 mmol) from Step 120 g at 0 °C was added Trifluoroacetic acid (1.5ml) in dichloromethane (15ml). The solution was stirred for 2 hours, allowed to warm to room temperature, then adjusted to pH 11 with 10% sodium hydroxide and extracted with dichloromethane. Then over sulfuric acid The organic extract was dried over magnesium and concentrated. The residue was chromatographed (silica gel, chloroform/methanol, 95:5) to give the free base of the title compound (300 mg, 82%): ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.42 ( t, J=6Hz, 3H), 2.18(m, 2H), 2.95(m, 1H), 3.58(m, 2H), 4.02(m, 2H), 4.15(q, J=6Hz, 2H), 6.75(t , J=3Hz, 1H), 7.95 (t, J=3Hz, 2H). MS (CI/NH ₃ ) m/e 209(M+H) ⁺ .

120i.5-Ethoxy-3-(2-(S)-azetidinylmethoxy)pyridine p-toluenesulfonate

The compound from Step 120h (100 mg, 0.484 mmol) was converted to a salt by treatment with p-toluenesulfonic acid in ethanol to afford the title compound (125 mg): mp 105 °C (dec); [α] ²⁵ _D = -6.8° (c=0.47, MeOH); ¹ H NMR (CDCl ₃ , 300MHz) δ1.40(t, J=6Hz, 3H), 2.35(s, 3H), 2.50(m, 2H), 3.95(q, J= 6Hz, 2H), 4.15(m, 2H), 4.38(d, J=3Hz, 2H), 4.98(br, 1H), 6.95(t, J=3Hz, 1H), 7.10(d, J=6Hz, 2H ), 7.65 (d, J=6Hz, 2H), 7.90 (d, J=3Hz, 1H), 8.02 (d, J=3Hz, 1H); MS (CI/NH ₃ ) m/z: 209 (M+ H) ⁺ . _Anal. Calcd. for _{C11H16N2O2.1.2TsOH.0.8H2O :} C, 54.28 _; H, _6.39 ; N, 6.53; Found: C, 54.60; H, 6.29; N, 6.20.

Example 121

2-Chloro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

121a.2-Chloro-3-(1-Boc-2-(S)-azetidinylmethoxy)pyridine

A solution of diethyl azodicarboxylate (1.04ml, 6.6mmol) was added to a solution of triphenylphosphine (1.73g, 6.6mmol) in THF (26ml) at 0°C, and the reaction mixture was stirred for 15 minutes. Then 1-BOC-2-(S)-azetidinemethanol (1.03 g, 5.5 mmol) and 2-chloro-3-pyridinol (785 mg, 6.0 mmol, Aldrich Chemical Co.) were added. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The solvent was removed and the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous potassium carbonate and brine, dried over magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, eluting with ethyl acetate:hexane (1:4-1:1), to give the title compound (611 mg). MS (DCI/ _NH3 ) m/z 299 (M+H) ⁺ .

121b.2-Chloro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

To a solution of 2-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine (469 mg, 1.66 mmol) from Step 121a in dichloromethane at 0 °C was added (5ml) in TFA (5ml) and the reaction mixture was stirred for 30 minutes. Volatile components were then removed in vacuo. The residue was treated with saturated aqueous potassium carbonate, then extracted with dichloromethane, dried over magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, eluting with chloroform:methanol:ammonium hydroxide (10:1:0-10:1:0.5) to give the free base of the title compound (217 mg). The base (156mg) was dissolved in dichloromethane (3ml) and the base was converted to a salt by treatment with saturated HCl in ether to give the title compound (142mg). mp 155-156°C; MS (DCI/NH ₃ ) m/z: 199, 201 (M+H) ⁺ , 216 (M+NH ₄ ) ⁺ . ¹ H NMR (D ₂ O, 300MHz) δ2.7-2.79 (m, 2H), 4.13-4.24 (m, 2H), 4.44-4.58 (m, 2H), 4.98 (m, 1H), 7.45 (dd, J = 4.8, 8.1 Hz, 1H), 7.59 (dd, J = 1.5, 8.2 Hz, 1H), 8.03 (dd, J = 1.4, 4.5 Hz, 1H). _Anal. Calcd. for _{C9H11N2OCl.1.0} HCl: C, 45.98; H, 5.14; _N , 11.91; Found: C, 45.76; H, 5.09; N, 11.64.

Example 122

2-Amino-3-(2(S)-azetidinylmethoxy)pyridine hydrochloride

122a.2-Fluoro-3-hydroxypyridine

2-Fluoro-3-hydroxypyridine (8.25 g, 75 mmol; from Aldrich) was dissolved in HF·pyridine (100 g, Aldrich) and cooled to 0°C. Sodium nitrite (5.4 g, 78 mmol) was added over 30 minutes. The solution was stirred for 30 minutes, then poured slowly into 300 ml of 25% sodium hydroxide at 0°C. The aqueous mixture was filtered and extracted with dichloromethane (6 x 75ml). The aqueous solution was adjusted to pH 6 with 20% aqueous sodium hydroxide, extracted with ethyl acetate (6 x 100 ml), then the combined ethyl acetate extracts were dried over magnesium sulfate and concentrated. The residue was chromatographed (silica gel, hexane/ethyl acetate (9:1-6:4) to obtain 3.93 g of the title compound. ¹ H NMR (CDCl ₃ , 300 MHz) δ7.75 (m, 1H), 7.37 (m , 1H), 7.11 (m, 1H). MS (DCI/NH ₃ ) m/z 114 (M+H) ⁺ , 131 (M+NH ₄ ) ⁺ .

122b.2-fluoro-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine

According to the method of Example 17a, but using 2-fluoro-3-hydroxypyridine and 1-Cbz-2-(S)-azetidinemethanol respectively instead of 5-bromo-9-chloropyridine-3- alcohol and 1-BOC-2-(S)-azetidinylmethanol. Yield 56%. ¹ H NMR (DMSO-d ₆ , 130°C, 300MHz) δ7.72(m, 1H), 7.55(m, 1H), 7.30-7.20(m, 5H), 7.17(m, 1H), 5.01(s, 1H), 4.56(m, 1H), 4.41(dd, J=11.11, 1H), 4.5(dd, J=10.68, 1H), 3.90-3.85(t, J=7.26, 2H), 2.42(m, 1H ), 2.25(m, 1H). MS (DCI/NH ₃ ) m/z 334 (M+H) ⁺ , 317 (M+NH ₄ ) ⁺ .

122c.2-fluoro-3-(2-azetidinylmethoxy)pyridine hydrochloride

2-Fluoro-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine (Step 122b, 1.1 g, 34.8 mmol) was mixed with 100 mg of 5% Pd/C in ethanol (25 ml ) were mixed, and the mixture was stirred under hydrogen for 16 hours. The mixture was filtered and concentrated. The crude product was chromatographed (silica gel, chloroform, 99:1:-94:6) to yield 480 g (76%) of the free base of the title compound. The base was converted to the salt by treatment with 1M HCl in ether. The salt was recrystallized 3 times from EtOH/ _Et2O to give 150 mg of ^the title compound1H NMR ( _D2O , 300MHz) δ 7.81 (m, 1H), 7.67 (m, 1H), 7.35 (m, 1H) , 4.97 (m, 1H), 4.5-4.48 (t, J=2.04Hz, 2H), 4.21-4.06 (m, 2H), 2.75-2.66 (tt, J=6.95Hz, 2H). MS (DCI/NH ₃ ) m/z: 183 (M+H) ⁺ ; 200 (M+NH ₄ ) ⁺ . _Anal. Calcd. for _{C9H11N2OF.HCl.0.3H2O} : C, _48.24 ; _H , 5.67; N, 12.50; Found: C, 84.30; H, 5.56; N, 12.15.

Example 123

6-cyano-3-(2(S)-azetidinylmethoxy)pyridine hydrochloride

123a. 3-Amino-6-bromopyridine

A mixture of 2-bromo-5-nitropyridine (30.75g, 151.5mmol), water (250ml) and acetic acid (110ml) was heated to 45°C. Iron powder (24.5 g, 439 mmol) was added at a rate to maintain the temperature below 53°C, and the mixture was stirred at 48°C ± 5°C for 1 hour. The mixture was cooled to room temperature and filtered through celite filter aid, washing with ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate, the combined organic portions were washed with saturated sodium carbonate and brine, dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was chromatographed (silica gel, hexane/ethyl acetate, 100:0-50:50) to obtain 20.4 g of the title compound: MS (CI/NH ₃ ) m/z 173 (M+H) ⁺ , 190 (M +NH ₄ ) ⁺ ; ¹ H NMR (CDCl ₃ , 300MHz) δ6.86-6.90 (dd, 1H, J=8.5, 2.4Hz), 7.21-7.23 (d, 1H, J=8.2Hz), 7.85-7.86 (d, 1H, J=3Hz).

123b.3-Acetoxy-6-bromopyridine

Under nitrogen, 18 g (104 mmol) of 3-amino-6-bromopyridine (from step 123a above) dissolved in 35 ml of dimethoxyethane was added to 25.6 ml of boron trifluoride ether cooled to -15 °C Compound (208mmol, Aldrich). Tert-butyl nitrite (14.7ml, 125mmol, Aldrich) was then added at a rate to maintain the temperature below 0°C. Dimethoxyethane (65ml) and dichloromethane (60ml) were then added to aid stirring. After standing at -10°C for 10 minutes, the reaction was warmed to 5°C and stirred for 30 minutes. Pentane (400ml) was added to the reaction mixture and the solid was collected by suction filtration, washed with cold diethyl ether, air dried and dissolved in 125ml of acetic anhydride. The resulting solution was heated to 100°C ± 5°C for 1 hour. The solvent was removed in vacuo, the residue was suspended in saturated aqueous sodium carbonate and extracted with ether. The ethereal extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The crude product was chromatographed on silica gel, eluting with 100:0-60:40 hexane:ethyl acetate, to obtain 13.6 g of the title compound: ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.20 (m, 1H), 7.51 ( d, J=8.5Hz, 1H), 7.38(dd, J=2.9, 7.5Hz, 1H), 2.35(s, 3H). MS(CI/NH ₃ ) m/e: 216(M+H) ⁺ , 233(M+NH ₄ ) ⁺

123c.2-Bromo-5-hydroxypyridine

The product from Step 123b (12.8 g, 60 mmol) was dissolved in 15% aqueous sodium hydroxide (50 mL) at 0°C and the solution was allowed to warm to room temperature and stirred for 60 minutes. After all starting material had been consumed, the solution was neutralized by adding 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The organic extract was washed with water and brine, then dried (magnesium sulfate), and the solvent was evaporated to give 9.8 g of the title compound: ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.12-7.16 (dd, 1H, J=3.2 Hz), 7.36- 7.39 (d, 1H, J=8.5Hz), 8.04-8.05 (d, 1H, J=2.4Hz). MS m/e: 174 (M+H) ⁺ .

123d.6-Bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

The product of Example 123c was coupled to 1-BOC-2-(S)-azetidinylmethanol using the method described in Example 17a. ¹ H NMR (CDCl ₃ , 300MHz) δ1.42(s, 9H), 2.20-2.43(m, 2H), 4.88(t, J=8.0Hz, 2H), 4.17(dd, J=3.0, 9.0Hz, 1H), 4.30-4.39 (m, 1H), 4.43-4.58 (m, 1H), 7.42 (t, J=2.0Hz, 1H), 8.25-8.32 (m, 2H). MS (DCI/NH ₃ ) m/e: 343 (M+H) ⁺ , 360 (M+NH ₄ ) ⁺ .

123e.6-cyano-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

Zinc cyanate (0.295 g, 2.50 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.249 g, 0.20 mmol) were added to the product of Example 123d (1.22 g, 3.60 mmol) in degassed DMF (10 ml). ) and heated at 80°C for 5 hours. The mixture was cooled to room temperature and poured into saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (400ml), dried (magnesium sulfate) and concentrated in vacuo. The crude product was chromatographed (silica gel, ethyl acetate/hexane 1/1) to give a colorless oil (0.784 g, 75%): ¹ H NMR (CDCl ₃ , 300 MHz) δ1.42 (s, 9H), 2.22 -2.42(m, 2H), 3.82-3.87(m, 2H), 3.18(dd, J=3.0, 9.0Hz, 1H), 4.38-4.45(m, 1H), 4.48-4.60(m, 1H), 7.32 -7.58 (m, 1H), 7.62 (d, J=11.5Hz, 1H), 8.42 (d, J=4.0Hz, 1H). MS (DCI/NH ₃ ) m/e: 290 (M+H) ⁺ , 307 (M+NH ₄ ) ⁺ .

123f.6-cyano-3-(2(S)-azetidinylmethoxy)pyridine hydrochloride

The product of Example 123e was deprotected and converted to the hydrochloride salt as described in Example 17b: ¹ H NMR (CDCl ₃ ) δ 2.66-2.74 (m, 2H), 4.02-4.19 (m, 2H) , 4.50(d, 2H, J=4.4Hz), 4.84-4.99(m, 1H), 7.63(dd, 1H, J=3.0, 11.5Hz), 7.97(d, 1H, J=8.8Hz), 8.48( d, 1H, J = 3.0 Hz). MS (CI/NH ₃ ) m/z: 190.00 (M+H) ⁺ , 207.00 (M+NH ₄ ) ⁺ . _Anal. Calcd. for _C10H11N3O · _1.0HCl · _0.1Et2O ·0.1H2O: C, 53.18; H, 5.66; N, _17.89 ; Found: C, 53.07; H, 5.46; N, 17.87.

Example 124

3-(2-(R)-Azetidinylmethoxy)-5-bromo-6-methylpyridine p-toluenesulfonate

124a. 5-Bromo-6-methyl-3-(1-BOC-2-(R)-azetidinylmethoxy)pyridine

A compound of 5-bromo-3-hydroxy-6-methylpyridine (1.10g, 5.85mmol) and potassium hydroxide (0.52g, 9.28mmol) in DMF (20ml) was heated at 80°C for 1 hour, and 1 -BOC-2-(R)-Methanesulfonyloxymethylazetidine (2.0 g, 5.86 mmol) in DMF (10 ml). The reaction mixture was heated at 80 °C overnight. After cooling to room temperature, the brown solution was diluted with ethyl acetate (150 ml), washed with distilled water and brine, dried (sodium sulfate), and concentrated in vacuo. The crude product was chromatographed (silica gel, 1:1 ethyl acetate:hexane) to give a colorless oil (1.18 g, 56%): ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.43 (s, 9H), 2.30 (m, 2H), 2.59(s, 3H), 3.88(t, 2H, J=7.5Hz), 4.10(dd, 1H, J=7.2Hz), 4.29(m, 1H), 4.50(m, 1H) , 7.44 (d, 1H, J = 2.7 Hz), 8.18 (d, 1H, J = 2.7 Hz); MS (DCI/NH ₃ ) m/z: 357 (M) ⁺ .

124b.3-(2-(R)-azetidinylmethoxy)-5-bromo-6-methylpyridine

A solution of the compound from Step 124a (0.5g, 1.40mmol) in dichloromethane (6ml) was cooled to 0°C in an ice bath and trifluoroacetic acid (3ml) was added dropwise through the dropping funnel. The reaction mixture was stirred at 0°C for 2 hours. The mixture was concentrated in vacuo and the resulting residue was dissolved in ethyl acetate (40ml) and washed with 1M potassium carbonate. The basic aqueous washes were combined, saturated with brine, and back-extracted several times with ethyl acetate to recover the desired product. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. The crude product was chromatographed (silica gel, 80:19:1 chloroform:methanol:ammonium hydroxide) to give a colorless oil (0.33 g, 92%). ¹ H NMR (CDCl ₃ , 300MHz) δ2.30(m, 3H), 2.57(s, 3H), 3.48(m, 1H), 3.71(q, 1H, J=8.0Hz), 4.01(m, 2H) , 4.28 (m, 1H), 7.41 (d, 1H, J=2, 7Hz), 8.15 (d, 1H, J=2.7Hz); MS (DCI/NH ₃ ) m/z: 257 (M) ⁺ .

124c. 3-(2-(R)-azetidinylmethoxy)-5-bromo-6-methylpyridine p-toluenesulfonate

A solution of 5-bromo-6-methyl-3-(2-(R)-azetidinylmethoxy)pyridine (0.32 g, 1.24 mmol) from Example 124b in ethanol (5 ml) Add p-toluenesulfonic acid monohydrate (0.23 g, 1.21 mmol). The reaction mixture was stirred at room temperature for half an hour and concentrated in vacuo. The residue was dissolved in methanol (2ml), triturated with diethyl ether, and the precipitate was collected by filtration and dried to give a white solid (0.48g, 91%): mp ^142-144 °C; [α] _D23 +5.2(c0.5, MeOH ); ¹ H NMR (D ₂ O 300MHz) δ2.39(s, 3H), 2.55(s, 3H), 2.67(q, 2H, J=8.5Hz), 4.09(m, 2H), 4.37(d, 2H, J=4.4Hz), 4.92(m, 1H), 7.35(d, 2H, J=7.7Hz), 7.68(d, 2H, J=8.5Hz), 7.75(d, 1H, J=2.8Hz) , 8.16 (d, 1H, J = 2.7 Hz). MS (DCI/ _NH3 ) m/z: 257 (M) ⁺ . _Anal. Calcd. _{for C10H13BrN2O.TsOH} : C, 47.56; H, 4.93; N, 5.62; Found: C, 47.42; H, 5.13; N, 6.59.

Example 125

5-Bromo-6-fluoro-3-(2-(R)-azetidinylmethoxy)pyridine

The free base of the title compound was prepared according to the procedure detailed in Example 31, substituting the enantiomeric species 1-tert-butoxycarbonyl-2-(2R)-azetidinemethanol for its 1-tert-butoxy Carbonyl-2-(2S)-azetidinemethanol. The p-toluenesulfonate salt was prepared by adding the equivalent p-toluenesulfonic acid monohydrate to 5-((2R)-azetidinylmethoxy)-3-bromo-2-chloropyridine . Volatiles were removed in vacuo. The residue was triturated with ether and dried under vacuum to give the title compound as a white solid: mp 238-240 °C; [α] _D ²¹ 8.4 (c0.5, MeOH); ¹ HNMR (DMSO-d ₆ ) δ 2.29 (s, 3H), 2.39(m, 1H), 2.52(m, 1H), 3.93(m, 2H), 4.36(m, 1H), 4.43(m, 1H), 4.73(m, 1H), 7.11( d, 2H, J=7.9Hz), 7.48(d, 2H, J=7.9Hz), 8.00(m, 1H), 8.08(dd, 1H, J=2.4, 4.9Hz), 8.85(br s, 2H) ; MS (DCI/NH ₃ ) m/z: 261, 263 (M+H) ⁺ . _Anal. Calcd. for _C9H10BrFN2O · _1.7TsOH · _0.5H2O : C, 44.17; H, 4.44; N, 5.10; Found: C, 44.07; H, 4.08; N, 4.70.

Example 126

5-Ethyl-6-fluoro-3-(2-(S)-azetidinylmethoxy)pyridine

126a. 3-Bromo-2-fluoro-5-nitropyridine

3-Bromo-2-chloro-5-nitropyridine (119g, 0.500mol, prepared according to the method of V.Koch and S.Schnatterer, Synthesis, 1990, 497-498), potassium fluoride (79.5g, 1.37mol) and tetraphenylphosphonium bromide (109g, 0.260mol) were mixed in acetonitrile (1.5L) and heated at reflux for 4 days until GLC showed 3-bromo-2-chloro-5-nitropyridine Consumed completely. The volume of the mixture was reduced to 750 mL in vacuo and the residual liquid was diluted with 2 L of diethyl ether. The mixture was filtered and the filtrate was concentrated. The residue was triturated with hot hexane and the combined hexane extracts were concentrated to give 62.8 g (54%) of the title compound: ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.14 (m, 2H).

126b.5-Amino-3-bromo-6-fluoropyridine

To 3-bromo-2-fluoro-5-nitropyridine (5.0 g, 23 mmol,) from step 126a above in methanol (100 mL) was added tin(II) chloride dihydrate. The mixture was heated at reflux for 3 hours. It was then cooled to room temperature and concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate and ethyl acetate to form an emulsion, which was filtered. Pour the filtrate into a separatory funnel and separate the layers. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated. Purification by chromatography (silica gel, hexane/ethyl acetate, 70:30) provided 3.61 g (83%) of the title compound as a yellow solid: mp 91-92 °C; ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.15 ( dd, J=2.5, 7.5Hz, 1H), (dd, J=2.0, 2.5Hz, 1H). MS (DCI/NH ₃ ) m/z: 191, 193 (M+H) ⁺ , 208, 210 (M+NH ₄ ) ⁺ .

126c.5-Amino-2-fluoro-3-vinylpyridine

To a stirred solution of 5-amino-2-fluoro-3-bromopyridine (3.25 g, 170 mmol) from step 126b above in toluene (20 ml) was added tributyl(vinyl)tin (Aldrich, 7.64 g, 20.4 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (Aldrich, 0.63 g, 1.7 mmol). The reaction mixture was stirred at 100°C for 24 hours. The solvent was removed in vacuo and the residue was purified by column chromatography (silica gel, ethyl acetate/hexane 4:6) to give the desired product as a beige solid (2.30 g, 98%): ¹ H NMR (CDCl ₃ , 300 MHz) δ3 .61(br s, 2H), 5.44(d, J=11.5Hz, 1H), 5.83(d, J=17.5Hz, 1H), 6.66(m, 1H), 7.18(dd, J=3.0, 5.0Hz , 1H), 7.52 (m, 1H); MS (CI/NH ₃ ) m/z 139 (M+H ⁺ ), 156 (M+NH ₄ ) ⁺

126d.5-Amino-3-ethyl-2-fluoropyridine

A solution of 5-amino-2-fluoro-3-vinylpyridine (2.30 g, 16.6 mmol) in methanol (50 ml) from step 126c above was added to 10% palladium on activated carbon (Aldrich, 0.1 g) in methanol ( 75ml) suspension. The mixture was placed under hydrogen (balloon) for 48 hours. The catalyst was removed by filtration and the solvent was evaporated to give the title compound as a beige solid (2.31 g, 99%): ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.22 (t, J = 7.5 Hz, 3H), 2.58 (q, J = 7.5Hz, 2H), 6.96(dd, J=3.0, 5.1Hz, 1H), 7.45(m, 1H); MS(CI/NH ₃ ) m/z: 141(M+H) ⁺ , 158(M+ NH ₄ ) ⁺ .

126e.5-Acetoxy-3-ethyl-2-fluoropyridine

Boron trifluoride etherate (Aldrich, 4.23ml, 34.5mmol) was added slowly to 5 from Step 126d above in 3:1 dimethoxyethane:dichloromethane (50ml) at -10°C. - in a stirred solution of amino-3-ethyl-2-fluoropyridine (2.30 g, 16.4 mmol). A solution of tert-butyl nitrite (Aldrich, 2.34 mL, 19.7 mmol) was added over 15 minutes while maintaining the reaction temperature below -5°C. The reaction mixture was allowed to warm to 0 °C and stirred for 30 minutes. Pentane (500ml) was added and the solid diazonium tetrafluoroborate was collected by filtration. The diazonium salt was dissolved in acetic anhydride (40ml) and heated at 95°C for 2 hours (nitrogen evolution was observed at 80°C). The solvent was evaporated and the residue was dissolved in ether (250ml) and washed with saturated aqueous sodium bicarbonate (2 x 150ml). The combined aqueous phases were extracted with diethyl ether (2 x 150ml). The combined organic phases were washed with brine (50 ml), dried (magnesium sulfate) and concentrated, and the crude product was purified by column chromatography (silica gel, ethyl acetate/hexane, 4:6) to give the title compound (2.22 g , 74%): ¹ H NMR (CDCl ₃ , 300MHz) δ1.26(t, J=7.5Hz, 3H), 2.32(s, 3H), 2.67(q, J=7.0Hz, 2H), 7.35(dd , J=2.5, 8.0 Hz, 1H), 7.84 (m, 1H); MS (CI/NH ₃ ) m/z: 184, (M+H) ⁺ ; 201 (M+NH ₄ ) ⁺ .

126f.3-Ethyl-2-fluoro-5-hydroxypyridine

To a stirred solution of 5-acetoxy-3-ethyl-2-fluoropyridine (2.22 g, 12.1 mmol) from step 126e in methanol (50 ml) was added potassium carbonate (0.84 g, 6.10 mmol). The reaction mixture was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was diluted with ether (100ml) and water (100ml). The phases were separated and the aqueous phase was neutralized (pH 7) by the addition of 1N aqueous hydrochloric acid and extracted with diethyl ether (2 x 100ml). The combined ether extracts were washed with brine (50ml), dried (sodium sulfate) and the solvent was evaporated. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexane, 4:6) to give the desired material (1.18 g, 69%) as an off-white solid: ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.24 ( t, J=7.5Hz, 3H), 2.67(q, J=7.5Hz, 2H), 7.24(dd, J=2.0, 5.0Hz, 1H), 7.62(m, 1H); MS(CI/ _NH3 ) m/z: 142, (M+H) ⁺ ; 159 (M+NH ₄ ) ⁺ .

126g.5-(1-tert-butoxy-(2S)-azetidinylmethoxy)-3-ethyl-2-fluoropyridine

Powdered potassium hydroxide (JT Baker, 0.34 g, 6.1 mmol) was added to 3-ethyl-2-fluoro-5-hydroxypyridine (0.53 g, 3.8 mmol) from Example 126f in DMF (10 ml ) solution, the reaction mixture was stirred at room temperature for 1.5 hours until potassium hydroxide dissolved. (S)-1-(tert-butoxycarbonyl)-2-p-toluenesulfonyloxymethyl)azetidine (1.28 g, 3.8 mmol) from Example 10c was added and the reaction was stirred at 80°C The mixture was 18 hours. After cooling to room temperature, the solution was diluted with water (50ml) and extracted with ethyl acetate (3x30ml). The combined organic extracts were washed with brine (25ml), dried (magnesium sulfate) and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexane, 3:7) to afford the title compound as a yellow oil (0.93 g, 79%). ¹ H NMR (CDCl ₃ , 300MHz) δ1.23(t, J=7.7Hz, 3H), 1.42(s, 9H), 2.33(m, 2H), 2.62(q, J=7.7Hz, 2H), 3.90 MS( CI/NH ₃ ) m/z: 311 (M+H) ⁺ , 328 (M+NH ₄ ) ⁺ .

126h.5-((2S)-azetidinylmethoxy)-3-ethyl-2-fluoropyridine p-toluenesulfonate

A solution of the coupled product (0.93g, 3.0mmol) from step 126 above was dissolved in anhydrous dichloromethane (10ml) and cooled to 0°C. Trifluoroacetic acid (Aldrich, 10ml) was added. The solution was stirred at 0°C for 1 hour. The reaction mixture was carefully poured into saturated aqueous sodium bicarbonate (50ml) and extracted with ethyl acetate (3 x 30ml). The combined organic extracts were washed with brine (25ml), dried (magnesium sulfate) and the solvent was evaporated. The crude product was purified by column chromatography (silica gel, methanol/dichloromethane, 1:9, then chloroform/methanol/ _NH4OH , 80:20:1) to afford the free base of the title compound as a yellow oil (0.22 g, 35%). The oil was dissolved in ethanol, cooled to 0°C, and p-toluenesulfonic acid monohydrate (Aldrich, 0.20 g, 1.0 mmol) was added. After stirring at 0 °C for 30 min, the solvent was evaporated and the residue was triturated with ether to give an off-white solid (0.27 g, 24% isolated from the free amine): mp 106-108 °C; [α] _D ²¹ -20.4 (c0.6, Dichloromethane) free base; ¹ H NMR (DMSO-d ₆ ) δ1.18 (t, 3H, J=7.5Hz), 2.28 (s, 3H), 2.39 (m, 1H), 2.50 (m, 1H) , 2.61(q, 2H, J=7Hz), 3.85(m, 1H), 3.95(m, 1H), 4.37(m, 2H), 4.70(m, 1H), 7.10(d, 2H, J=7.5Hz ), 7.47(d, 2H, J=7.5Hz), 7.54(dd, 1H, J=3.5Hz), 7.78(m, 1H), 8.83(br s, 2H); MS(CI/NH ₃ )m/ z: 211(M+H) ⁺ , 228(M+NH ₄ ) ⁺ . _Anal . Calcd. for _C11H15FN2O - _1.5TsOH : C, 55.11; H, 5.81; N, 6.24; Found: C, 54.94; H, 5.86; N, 6.23.

Example 127

2-Chloro-3-methyl-5-(2-(R)azetidinylmethoxy)pyridine citrate

Following the procedure of Example 25, steps a and b, but substituting (R)-1-tert-butoxycarbonyl-2-azetidinemethanol for (S)-1-tert-butoxycarbonyl-2-azepam Heterobutane methanol, preparation of the title compound: mp 104-106 °C; [α] _D ²⁵ +10.3° (c0.3, MeOH); MS (DCI/NH ₃ ) m/z: 213 (M+H) ⁺ . ¹ H NMR (D ₂ O300MHz) δ2.27(d, J=10.5Hz, 1H), 2.37(s, 3H), 2.41-2.91(m, 8H), 4.08-4.13(m, 2H), 4.40(d , J=4Hz, 1H), 4.93(m, 1H), 7.49(d, J=3.1Hz, 1H), 7.97(d, J=3.0Hz, 1H); C ₁₀ H ₁₃ N ₂ OCl·C ₆ H Anal. Calcd. for ₈ O ₇ : C, 47.45; H, 5.19; N, 6.92; Found: C, 47.16; H, 5.48; N, 7.08.

Example 128

5-(2-(R)-Azetidinylmethoxy)-2-bromo-pyridine p-toluenesulfonate

128a. 5-Amino-2-bromopyridine

A mixture of 2-bromo-5-nitropyridine (Aldrich, 30.75g, 151.5mmol), water (250ml) and acetic acid (110ml) was heated to 45°C. Iron powder (24.5 g, 439 mmol) was added at a rate to maintain the temperature below 53°C, and the mixture was then stirred at 48°C ± 5°C. The mixture was cooled to room temperature and filtered through celite, the filter cake was washed with ethyl acetate, the aqueous mixture was extracted with ethyl acetate, the combined organic portions were washed with saturated sodium carbonate and brine, dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was chromatographed on silica gel, eluting with 100:0-50:50 hexane/ethyl acetate, to obtain 20.4 g of the title compound: ¹ H NMR (CDCl ₃ , 300 MHz) δ6.88 (dd, 1H, J=8.5 , 2.4Hz), 7.22(d, 1H, J=8.2Hz), 7.85(d, 1H, J=3Hz); MS(CI/NH ₃ ) m/z 173(M+H) ⁺ , 190(M+ NH ₄ ) ⁺ ;

128b.5-Acetoxy-2-bromopyridine

Under nitrogen, 18 g (104 mmol) of 5-amino-2-bromopyridine (from step 128a above) dissolved in 35 ml of DME was added to 25.6 ml of boron trifluoride etherate (208 mmol, Aldrich )middle. Tert-butyl nitrite (14.7ml, 125mmol, Aldrich) was then added at a rate to maintain the temperature below 0°C. Then DME (65ml) and dichloromethane (60ml) were added. After 10 minutes at -10°C the reaction was warmed to 5°C and stirred for 30 minutes. Pentane (400ml) was added to the reaction mixture, and the solid was collected by suction filtration, washed with cold ether, air-dried, and dissolved in 125ml of acetic anhydride, and the resulting solution was heated to 100°C ± 5°C for 1 hour. The solvent was removed in vacuo, the residue was suspended in saturated aqueous sodium carbonate and extracted with ether. The ether solution was dried over magnesium sulfate, the solvent was evaporated in vacuo, and the residue was chromatographed on silica gel, eluting with 100:0-60:40 hexane:ethyl acetate, to give 13.6 g of the title compound: ¹ HNMR (CDCl ₃ , 300 MHz) δ2 .35 (s, 3H), 7.37 (dd, 1H), 7.51 (d, 1H), 8.19-8.21 (d, 1H). MS m/z: 216(M+H) ⁺ , 233(M+NH ₄ ) ⁺

128c.2-Bromo-5-hydroxypyridine

The product from Step 128b (12.8 g, 60 mmol) was dissolved in 15% aqueous sodium hydroxide (50 mL) at 0°C and the solution was allowed to warm to room temperature and stirred for 60 minutes. After all starting material had been consumed, the solution was neutralized by adding 1N hydrochloric acid. The aqueous mixture was extracted with ethyl acetate (3 x 200ml). The organic extract was washed with brine (4×50ml), water (2×50ml), dried (magnesium sulfate), and the solvent was evaporated to give 9.8g of the title compound: ¹ H NMR (CDCl ₃ , 300MHz) δ7.14 (dd, 1H, J = 3.2 Hz), 7.37 (d, 1H, J = 8.5 Hz), 8.04 (d, 1H, J = 2.4 Hz). MS (CI/ _NH3 ) m/z: 174 (M+H) ⁺ .

128d.5-(2-(1-Boc-(R)-azetidinylmethoxy)-2-bromopyridine

2-Bromo-5-hydroxypyridine (0.130 g, 0.75 mmol) from Step 128c above was mixed with Boc-(R)-(tosyloxymethyl base) azetidine (0.255g, 0.75mmol) to obtain a colorless oil (0.208g, yield 81.3%). ¹ H NMR (CDCl ₃ , 300MHz) δ1.41(s, 9H), 2.20-2.42(m, 2H, blurred by solvent), 3.88(t, 2H, J=7.5Hz), 4.11(dd, 1H, J=2.9, 10.0Hz), 4.32(m, 1H), 4.50(m, 1H), 7.16(dd, 1H, J=3.2, 8.7Hz), 7.37(d, 1H, J=8.8Hz), 8.11( d, 1H, J=3.8Hz),; MS (CI/NH ₃ ); m/z 343 (M+H) ⁺ , 360 (M+NH ₄ ) ⁺ ;

128e. 5-(2-(R)-azetidinylmethoxy)-2-bromopyridine p-toluenesulfonate

The product from step 128d (0.17g, 0.52mmol) was dissolved in dichloromethane (5.6ml) and cooled to 0°C. Trifluoroacetic acid (1.4 ml) was then added, and the mixture was stirred at 0°C for 2 hours. The solvent was removed under reduced pressure, the residue was dissolved in brine (25ml) and extracted with a 3:1 mixture of chloroform/isopropanol (3x20ml). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to give the free base as a colorless oil (0.127 g, 100% yield). The free base (0.123g, 0.506mmol) was dissolved in ethanol (10ml), cooled to 0°C, and treated with p-toluenesulfonic acid (0.096g, 0.505mmol). After stirring at 0 °C for 30 min, ethanol was removed to give the title compound (0.209 g, yield 100%) as a white solid: mp 174-176 °C; [α] _D ²⁵ +5.2 (c0.9, methanol); ¹ H NMR (DMSO, 300MHz) δ2.29(s, 3H), 2.34-2.59(m, 2H), 3.82-4.04(m, 2H), 4.29-4.46(m, 2H), 4.74(m, 1H), 7.11 (d, 2H, J=8.1Hz), 7.42-7.51(m, 3H), 7.61(d, 1H, J=8.9Hz), 8.19(d, 1H, J=3.4Hz), 8.79-8.96(bs, 1H); MS (CI/NH ₃ ) m/z: 243 (M+H) ⁺ , 260 (M+NH ₄ ) ⁺ . _Anal. Calcd. for _{C9H11BrN2O.TsOH} : C, 46.27; H, 4.61; N, _6.75 ; Found: C, 46.65; H, 4.63; N, 6.37.

Example 129

5-((2R)--Azetidinylmethoxy)-2-fluoro-3-vinylpyridine p-toluenesulfonate

129a. 5-(1-Boc-2-(R)-azetidinylmethoxy)-3-vinyl-2-fluoropyridine

Following the procedure of Example 131 below, but substituting the enantiomer (R)-1-tert-butoxycarbonyl-2-p-toluenesulfonyloxymethyl)azetidine from Example 1 ( S)-1-tert-butoxycarbonyl-2-p-toluenesulfonyloxymethyl)azetidine, the title compound was prepared as a clear oil in 76% yield: ¹ H NMR (CDCl ₃ , 300 MHz )δ1.42(s, 9H), 2.24-2.42(m, 2H), 3.92(m, 1H), 4.13(dd, J=3.0, 7.0Hz, 2H), 4.35(m, 1H), 4.54(m , 1H), 5.49(d, J=11.0Hz, 1H), 5.89(d, J=18.0Hz, 1H), 6.75(m, 1H), 7.47(dd, J=2.7, 5.1Hz, 1H), 7.76 (m, 1H); MS (CI/NH ₃ ); m/z 309 (M+H) ⁺ , 326 (M+NH ₄ ) ⁺ .

129b. 5-(2-(R)-azetidinylmethoxy)-3-vinyl-2-fluoropyridine p-toluenesulfonate

To a solution of the product from Step 129a above (0.21 g, 0.7 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) at 0°C. After stirring at 0°C for 1 hour, the volatile components were removed in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3X). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated. Column chromatography of the residue (silica gel, methanol/dichloromethane, 1:9, then chloroform/methanol/ammonium hydroxide, 80:20:1) afforded the desired material as a yellow oil (0.10 g, 68%) . The oil was dissolved in ethanol, cooled to 0°C, and p-toluenesulfonic acid monohydrate (0.09 g, 0.5 mmol) was added. After stirring at 0°C for 30 minutes, the solvent was evaporated and the solid was triturated with diethyl ether to give the title compound (0.05 g, 20% isolated from the free amine) as a pale yellow solid: mp 84-85°C; [α] _D ²³ +12.6( c0.5, MeOH); ¹ H NMR (DMSO-d ₆ , 300MHz) δ2.28 (s, 3H), 2.40 (m, 1H), 2.51 (m, 1H), 3.86-4.02 (br m, 2H) , 4.38(m, 2H), 4.74(m, 1H), 5.60(d, J=11.0Hz, 1H), 6.09(d, J=17.5Hz, 1H), 6.75(m, 1H), 7.11(d, J=8.0Hz, 2H), 7.48(d, J=8.0Hz, 2H), 7.86(m, 2H), 8.85(br s, 2H); MS(CI/NH ₃ ) m/z: 209(M+ H) ⁺ , 226(M+NH ₄ ) ⁺ . _Anal. Calcd. for _{C11H13FN2O.TsOH.0.3H2O} : _C , 56.03; H, 5.64; N, _7.26 ; Found: C, 55.87; H, 5.43; N, 7.20.

Example 130

3-(2-(S)-azetidinylmethoxy)-5-(3-propenyl)-pyridine hydrochloride

130a.3-(1-Boc-2-(S)-azetidinylmethoxy)-5-(3-propenyl)-pyridine

Tetrakis(triphenylphosphine)palladium(O) (100mg), allyltributyltin (1.72ml, 5.54mmol) were added to 3-(1-Boc-2-(S)-azetidinylmethoxy )-5-bromopyridine (0.95 g, 2.77 mol, from Example 12, step a). The mixture was stirred and refluxed for two days. The solvent was evaporated, and the residue was chromatographed (silica gel, hexane: ethyl acetate 5:1-1:1) to give an oil (250 mg, 30%): ¹ H NMR (CDCl ₃ , 300 MHz) δ1.42 (s, 9H), 2.22-2.42(m, 2H), 3.37(d, 2H, J=7.0Hz), 3.87-3.92(m, 2H), 4.16(m, 1H), 4.30(m, 1H), 4.50(m , 1H), 5.07-5.17 (m, 2H), 5.9 (m, 1H), 7.07 (m, 1H), 8.08 (m, 1H), 8.19 (d, 1H, J=3.0Hz). MS (CI/ _NH3 ) m/z 305 (M+H) ⁺ .

130b.3-(2-(S)-azetidinylmethoxy)-5-(3-propenyl)-pyridine

The product from step 130a above (250mg, 0.82mmol) in _CH2Cl2 ( _2ml ) was cooled to 0°C and TFA (1.1ml) was added carefully. The reaction mixture was stirred at 0°C for 40 minutes. The mixture was allowed to warm to room temperature and stirred for 30 minutes. After neutralizing with 1% aqueous sodium hydroxide solution, the reaction mixture was extracted with dichloromethane (3X). The combined organic layers were dried over magnesium sulfate, concentrated and chromatographed (silica gel, dichloromethane/methanol/ammonium hydroxide, 10:0.3:0-10:1:0.03) to give a pale yellow oil (365 mg, 69%): ¹ H NMR (CDCl ₃ , 300MHz) δ2.28(m, 1H), 2.42(m, 1H), 3.37(d, 2H, J=6.5Hz), 3.52(m, 1H), 3.76(m, 1H) , 4.04(m, 2H), 4.30(m, 1H), 5.06-5.16(m, 2H), 5.94(m, 1H), 7.04(m, 1H), 8.08(d, 1H, J=2.0Hz), 8.18 (d, 1H, J = 3.0 Hz); MS (CI/NH ₃ ) m/z: 239 (M+H ⁺ ).

130c.3-(2-(S)-azetidinylmethoxy)-5-(3-propenyl)-pyridine hydrochloride

Hydrogen chloride (1.0M in ether) was carefully added to the product of step 130b above to afford the title compound: ¹ H NMR (D ₂ O) δ 2.70 (q, 2H, J = 8.5 Hz), 3.49 (d, 2H , J=6.5Hz), 4.02-4.20(m, 2H), 4.44(d, 2H, J=4.5Hz), 4.95(m, 1H), 5.12-5.20(m, 2H), 6.05(m, 1H) , 7.53 (s, 1H), 8.15 (s, 1H), 8.24 (d, 1H, J = 2.0 Hz); MS (CI/NH ₃ ) m/z: 205 (M+H) ⁺ . _{Anal. Calcd} . _{for C12H16N2O.2HCl.0.2H2O} : C, 54.14; H, 6.82; N, 10.52; Found: C, 54.30; H, 6.82; N, 10.49. ; [α] ²⁵ _D -3.5 (c0.63, MeOH).

Example 131

5-(2-(S)-Azetidinylmethoxy)-3-vinyl-2-fluoropyridine p-toluenesulfonate

131a. 3-Bromo-2-fluoro-5-nitropyridine

3-Bromo-2-chloro-5-nitropyridine (119g, 0.500mol, prepared according to the method of V.Koch and S.Schnatterer, Synthesis, 1990, 497-498), potassium fluoride (79.5g, 1.37 mol) and tetraphenylphosphonium bromide (109 g, 0.260 mol) were mixed in acetonitrile (1.5 L) and heated at reflux for 4 days until GLC showed that 3-bromo-chloro-5-nitropyridine was completely consumed . The volume of the mixture was reduced to 750 mL in vacuo, then diluted with 2 L of ether. The mixture was filtered and the filtrate was concentrated. The residue was triturated with hot hexanes (2 x 1 L, then 2 x 0.5 L) and the combined hexane extracts were concentrated to give 62.8 g (54%) of the title compound: ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.14 (m, 2H).

131b.5-Amino-3-bromo-6-fluoropyridine

To 3-bromo-2-fluoro-5-nitropyridine (5.0 g, 23 mmol,) from step 131a above in methanol (100 mL) was added tin(II) chloride dihydrate. The mixture was heated at reflux for 3 hours. It was then cooled to room temperature and concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate and ethyl acetate to form an emulsion, which was filtered. Pour the filtrate into a separatory funnel and separate the layers. The aqueous phase was extracted with ethyl acetate (2X). The combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated. Purification by chromatography (silica gel, hexane/ethyl acetate, 70:30) afforded 3.61 g (83%) of the title compound as a yellow solid: mp 91-92 °C; ¹ HNMR (CDCl ₃ , 300 MHz) δ 7.15 (dd , J=2.5, 7.5Hz, 1H), (dd, J=2.0, 2.5Hz, 1H). MS (CI/NH ₃ ) m/z: 191, 193 (M+H) ⁺ , 208, 210 (M+NH ₄ ) ⁺ .

131c.5-Amino-3-vinyl-2-fluoropyridine

To a stirred solution of 5-amino-3-bromo-2-fluoropyridine (3.25 g, 17.0 mmol) in toluene (20 mL) from Step 131b above was added tributyl(vinyl)tin (7.64 g, 20.4 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (Aldrich, 0.63 g, 1.7 mmol). The reaction mixture was stirred at 100°C for 24 hours. The solvent was removed in vacuo and the residue was purified by column chromatography (silica gel, ethyl acetate/hexane 4:6) to afford the title compound as a beige solid (2.30 g, 98%): ¹ HNMR (CDCl ₃ , 300 MHz) δ 3.61 (br s, 2H), 5.44(d, J=11.5Hz, 1H), 5.83(d, J=17.5Hz, 1H), 6.66(m, 1H), 7.18(dd, J=3.0, 5.0Hz, 1H ), 7.52 (m, 1H); MS (CI/NH ₃ ) m/z 139 (M+H ⁺ ), 156 (M+NH ₄ ) ⁺

131d.5-Acetoxy-3-vinyl-2-fluoropyridine

Boron trifluoride etherate (Aldrich, 5.60ml, 45.6mmol) was added slowly to the product from step 131c above in 3:1 dimethoxyethane:dichloromethane (50ml) at -10°C (3.00g, 21.7mmol) solution, tert-butyl nitrite (Aldrich, 3.10ml, 26.0mmol) solution was added over 15 minutes while maintaining the reaction temperature below -5°C. The reaction mixture was allowed to warm to 0 °C and stirred for 30 minutes. Pentane (500ml) was added and the solid diazonium tetrafluoroborate was collected by filtration. The diazonium salt was dissolved in acetic anhydride (40ml) and heated at 95°C for 2 hours (nitrogen evolution was observed at about 85°C). After cooling to room temperature, the dark mixture was concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ether (3 x 150ml). The combined organic extracts were washed with brine (50 mL), dried (magnesium sulfate), and concentrated, and the crude product was purified by column chromatography (silica gel, ethyl acetate/hexane, 40:60) to afford the title compound ( 1.51 g, 40%): ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.35 (s, 3H), 5.54 (d, J=11.0Hz, 1H), 5.90 (d, J=18.0Hz, 2H), 6.75 (m, 1H), 7.66 (dd, J=2.0, 5.0 Hz, 1H); MS (CI/NH ₃ ) m/z: 182, (M+H) ⁺ ; 199 (M+NH ₄ ) ⁺ .

131 e. 3-vinyl-2-fluoro-5-hydroxypyridine

To a stirred solution of the product from Step 131d above (1.40 g, 7.70 mmol) in methanol (50 mL) was added potassium carbonate (0.53 g, 3.8 mmol). The reaction mixture was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was diluted with ether (100ml) and water (100ml). The phases were separated, the aqueous phase was neutralized (pH≈7) by addition of 1N aqueous hydrochloric acid and extracted with diethyl ether (2×100ml). The combined ether extracts were washed with brine (50ml), dried (magnesium sulfate) and concentrated. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexane, 40:60) to afford the title compound (0.81 g, 76%) as an off-white solid: ¹ H NMR (CDCl ₃ , 300 MHz) δ 5.50 (d , J=11.0Hz, 1H), 5.87(d, J=17.5Hz, 1H), 6.75(m, 1H), 7.72(dd, J=3.0, 5.0Hz, 1H), 7.69(m, 1H); (CI/NH ₃ ) m/z: 140, (M+H) ⁺ ; 157 (M+NH ₄ ) ⁺ .

131f.5-(1-Boc-(2S)-azetidinylmethoxy)-3-vinyl-2-fluoropyridine

Powdered potassium hydroxide (0.36 g, 6.5 mmol) was added to a solution of the product from step 131e above (0.60 g, 4.3 mmol) in DMF (10 ml) and the reaction mixture was stirred at room temperature for 1.5 hours until potassium hydroxide dissolve. 1-Boc-2-(S)-azetidinemethyl-p-toluenesulfonate (1.96 g, 4.3 mmol, from Example 10) was added and the reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was diluted with water (50ml) and extracted with ethyl acetate (3x30ml). The combined organic extracts were washed with brine (25ml) and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, dichloromethane/methanol, 98:2) to give the desired material as a yellow oil (1.44 g, >100%). ¹ H NMR (CDCl ₃ , 300MHz) δ1.42(s, 9H), 2.45(m, 2H), 3.90(m, 1H), 4.13(dd, J=3.0, 7.5Hz, 2H), 4.35(m, 1H), 4.54(m, 1H), 5.49(d, J=11.0Hz, 1H), 5.89(d, J=17.5Hz, 1H), 6.74(m, 1H), 7.47(m, 1H), 7.76( m, 1H); MS (CI/NH ₃ ) m/z: 309 (M+H) ⁺ , 326 (M+NH ₄ ) ⁺ .

131g.5-(2-(S)-azetidinylmethoxy)-3-vinyl-2-fluoropyridine p-toluenesulfonate

Trifluoroacetic acid (10 mL) was added to a solution of the coupled product from Step 1131f above (1.44 g, 4.70 mmol) in dichloromethane (10 mL) at 0°C. After stirring at 0°C for 1 hour, the volatile components were removed in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3X). The combined organic extracts were washed with brine, dried (magnesium sulfate), and concentrated. The residue was purified by column chromatography (silica gel, methanol/dichloromethane, 1:9, then chloroform/methanol/ _NH4OH , 80:20:1) to give the desired material as a yellow oil (0.37 g, 41% ): [α] _D ²⁵ -2.8 (c0.4, MeOH). The oil was dissolved in ethanol, cooled to 0°C, and p-toluenesulfonic acid monohydrate (0.34 g, 1.8 mmol) was added. After stirring at 0°C for 30 minutes, the solvent was evaporated and the solid was triturated with diethyl ether to give the title compound (0.30 g, 48% isolated from the free amine) as a white solid: mp 251-253°C; ¹ H NMR (DMSO-d ₆ , 300MHz) δ2.29(s, 3H), 2.38(m, 1H), 2.43(m, 1H), 3.86-4.02(m, 2H), 4.40(m, 2H), 4.74(m, 1H), 5.60( d, J=11.0Hz, 1H), 6.09(d, J=16.5Hz, 1H), 6.74(m, 1H), 7.11(d, 1H, J=8.5Hz), 7.48(d, J=8.0Hz, 2H), 7.87 (m, 2H), 8.86 (br s, 2H); MS (CI/NH ₃ ) m/z: 209 (M+H) ⁺ , 226 (M+NH ₄ ) ⁺ . _{Anal. Calcd} . for _{C11H13FN2O.1.3TsOH} : C, 55.87; H, 5.46; N, 6.48; Found: C, 56.23; H, 5.68; N, 6.28.

Example 132

5-nitro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

132a. 3-Benzyloxy-5-bromopyridine

Sodium hydride (60% in mineral oil) (40.9 g, 1.0225 mol) in 800 ml DMF was cooled to 0°C and benzyl alcohol (105 ml, 1.014 mol) was added slowly. The reaction mixture was stirred at 20°C for 1 hour, then 3,5-dibromopyridine (200.4 g, 846 mmol) was added and the mixture was stirred for 16 hours. The mixture was quenched with saturated ammonium chloride (500ml), diluted with 400ml of water and extracted with diethyl ether (5 x 300ml). The combined ether extracts were washed with 50% brine and dried (magnesium sulfate). The solvent was evaporated in vacuo, and the crude product was recrystallized from diethyl ether to give 161 g (72%) of the title compound: mp 63-68°C; ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.37-8.27 (m, 2H), 7.5- 7.35 (m, 6H), 5.1 (s, 1H); MS (DCI/NH ₃ ) m/z: 264, 266 (M+H) ⁺ .

132b.3-Amino-5-benzyloxypyridine

The product from step 132a (41.3 g, 156 mmol), copper(I) bromide (22.43 g, 156 mmol), methanol (275 ml), and liquid ammonia (50 ml) were mixed in a stainless steel reactor and heated to 130° C. for 24 hours. The mixture was allowed to cool to room temperature, then concentrated. The residue was suspended in 300 ml saturated aqueous sodium carbonate and extracted with dichloromethane (4 x 500 ml). The combined dichloromethane solutions were washed with brine, dried (magnesium sulfate), and concentrated. The crude product was chromatographed (silica gel; hexane/ethyl acetate, 9:1-7:3) to give 15.6 g (50%) of the title compound: ¹ H NMR (CDCl ₃ , 300 MHz) δ8.21-8.29 (m, 2H), 7.44-1.26 (m, 6H), 5.10 (s, 2H); MS (DCI/NH ₃ ) m/z: 201 (M+H) ⁺ .

132c.3-Amino-5-hydroxypyridine

The product of Example 132b (15.47 g, 77.25 mmol) in methanol (25 ml) was stirred under hydrogen in the presence of 5% Pd/C (100 mg) for 48 hours, the mixture was filtered and concentrated, and the crude product was then separated into layers Analysis (silica gel, chloroform/methanol, 9:1) gave 4.5 g (53%) of the title compound: MS (DCI/NH ₃ ) m/z: 111 (M+H) ⁺ ; 128 (M+NH ₄ ) ⁺ . 1H NMR (CDCl ₃ , 300MHz) δ 7.4 (d, J=3Hz, 1H), 7.3 (d, J=2.5Hz, 1H), 6.33 (dd, J=2.6Hz, 1H).

132d.3-Hydroxy-5-nitropyridine

Potassium persulfate (56.8 g, 210 mmol) was triturated into 31.5 mL of concentrated sulfuric acid and this solution was added to a solution of the product from Example 132c (2.75 g, 25 mmol) in concentrated sulfuric acid (27 mL). The mixture was allowed to stand for 72 hours, then poured onto ice and adjusted to pH 6 with concentrated ammonium hydroxide. The solution was extracted with ethyl acetate (4 x 100ml), then the ethyl acetate extract was dried (sodium sulfate) and concentrated. The crude product was chromatographed (silica gel, chloroform/methanol, 99:1-9:1) to obtain 1.65 g (47%) of the title compound: ¹ H NMR (CDCl ₃ , 300 MHz) δ8.81 (d, J=3Hz, 1H ), 8.51 (d, H=3Hz, 1H), 7.82 (dd, J=2.5Hz, 1H). MS (DCI/NH ₃ ) m/z: 141 (M+H) ⁺ ; 158 (M+NH ₄ ) ⁺ .

132e.5-Nitro-3-(1-Boc-2-(S)-azetidinylmethoxy)pyridine

According to the method of Example 17a, 1-Boc-2-(S)-azetidinylmethanol (868 mg, 4.64 mol) was mixed with 3-hydroxy-5-nitropyridine (500 mg, 3.57 mmol) coupling. The solvent was removed, and the residue was chromatographed (silica gel; hexane/ethyl acetate, 5:1) to obtain the title compound (800 mg, 73%): ¹ H NMR (CDCl ₃ , 300 MHz) δ1.45 (s, 9H), 2.56(m, 2H), 4.52(m, 4H), 4.82(m, 1H), 8.25(t, J=3Hz, 1H), 8.65(d, J=3Hz, 1H), 9.05(d, J=3Hz , 1H). MS (DCI/ _NH3 ) m/z: 310 (M+H) ⁺ .

132f.5-nitro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

To the product of Example 132e (800 mg, 2.58 mmol) in dichloromethane was added HCl/ether at 0°C and the solution was stirred for 1 hour. The solvent was evaporated and the residue was recrystallized from ethanol/ether to give the title compound (750 mg): mp 162-164°C (dec); ¹ HNMR (D ₂ O 300MHz) δ 2.45 (m, 2H), 4.62 (m, 4H), 4.96(m, 1H), 8.26(t, J=3Hz, 1H), 8.75(d, J=3Hz, 1H), 9.25(d, J=3Hz, 1H); MS(APCI) m/z : 210(M+H) ⁺ . _{Anal. Calcd} . _{for C9H12ClN3O3-0.30HCl} : C, 42.13; H, 4.83; N, 16.38; Found: C, 42.28; H, 4.87; N, 16.24.

Compounds of the above-listed embodiments and embodiments within the scope of formula (I) with various variables cited herein are useful in the prevention or treatment of pain, in addition to certain pains as indicated herein. The compounds are also useful in the treatment of neuronal cell death and in the treatment of inflammation. Applicants also claim those (S) compounds and (R) compounds that were not previously claimed or disclosed.

Claims (36)

1. Formula IA compound or its pharmaceutically acceptable salt are used in the preparation of the medicine for treating or controlling the pain of mammals including people Wherein the stereochemical structure of Z, Y, X and 2-azetidine is selected from respectively: H, H, Me(S); H, H, Me(R); H, H, CN(S); H, H, Cl(S); H, H, Cl(R); H, H, Br(R); H, H, F(S); H, H, F (R); H, H, CHF ₂ (S); H, H, OMe(R); H, Me, Cl(S); H, Me, Cl(R); H, Et, F(S); H, Vinyl, Cl(S); H, Vinyl, Cl(R); H, Vinyl, F(S); H, Vinyl, F(R); H, ethynyl, Cl(S); H, ethynyl, Cl(R); H, Cl, Cl(S); H, Cl, Cl(R); H, Cl, F(S); H, Br, Me(S); H, Br, Me(R); H, Br, Cl(S); H, Br, Cl(R); H, Br, F(S); H, Br, F (R); H, Me, H(R); H, n-Pr, H(S); H, Vinyl, H(S); H, Vinyl, H(R); H, 3-propenyl, H(S); H, Cl, H(R); H, F, H(S); H, NO ₂ , H(S); H, OEt, H(S); Cl, H, H(S); Cl, H, H(R); F, H, H(S); F, H, F(S); F, H, Me(S); and F, H, Me(R). 2. The use according to claim 1, wherein the compound is selected from the (S) enantiomer. 3. The use according to claim 1, wherein said compound is selected from the (R) enantiomer. 4. The use of claim 1, wherein Z is H, Y is H and X is selected from chlorine and fluorine. 5. The use of claim 4, wherein the compound is 5-((2R)-azetidinylmethoxy)-2-chloropyridine or a pharmaceutically acceptable salt thereof. 6. The use of claim 4, wherein the compound is 5-((2R)-azetidinylmethoxy)-2-fluoropyridine or a pharmaceutically acceptable salt thereof. 7. A compound of formula IA or a pharmaceutically acceptable salt thereof: Wherein the stereochemical structure of Z, Y, X and 2-azetidine is selected from respectively: H, H, Me(S); H, H, Me(R); H, H, CN(S); H, H, Cl(S); H, H, Cl(R); H, H, Br(R); H, H, F(S); H, H, F (R); H, H, CHF ₂ (S); H, H, OMe(R); H, Me, Cl(S); H, Me, Cl(R); H, Et, F(S); H, Vinyl, Cl(S); H, Vinyl, Cl(R); H, Vinyl, F(S); H, Vinyl, F(R); H, ethynyl, Cl(S); H, ethynyl, Cl(R); H, Cl, Cl(S); H, Cl, Cl(R); H, Cl, F(S); H, Br, Me(S); H, Br, Me(R); H, Br, Cl(S); H, Br, Cl(R); H, Br, F(S); H, Br, F (R); H, Me, H(R); H, n-Pr, H(S); H, Vinyl, H(S); H, Vinyl, H(R); H, 3-propenyl, H(S); H, Cl, H(R); H, F, H(S); H, NO ₂ , H(S); H, OEt, H(S); Cl, H, H(S); Cl, H, H(R); F, H, H(S); F, H, F(S); F, H, Me(S); and F, H, Me(R). 8. The compound of claim 7, wherein the pharmaceutically acceptable salt is selected from the group consisting of p-toluenesulfonate, benzoate, mesylate, naphthalenesulfonate, citrate or fumarate. 9. The compound of claim 7, wherein the pharmaceutically acceptable salt is the tosylate salt. 10. The compound of claim 7, wherein X is chlorine, Z is H and Y is selected from the group consisting of H, chlorine, bromine and methyl. 11. The compound of claim 10, wherein the stereochemistry of the 2-azetidine is (R). 12. The compound of claim 11, wherein Y is H. 13. The compound of claim 7, wherein X is fluoro, Z is H and Y is selected from the group consisting of H, vinyl, bromo and methyl. 14. The compound of claim 13, wherein the stereochemistry of the 2-azetidine is (R). 15. The compound of claim 14, wherein Y is H. 16. A pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable excipient. 17. Use of the compound of claim 7 in the preparation of a medicament for inhibiting neuronal cell death. 18. Use of the compound of claim 7 for the manufacture of a medicament for the treatment or prevention of inflammation. 19. Use of a compound of claim 7 and an opioid or NSAID analgesic for the manufacture of a medicament for the treatment or control of pain. 20. The use of claim 19, wherein said compound is defined as Z is H, Y is H, and X is selected from the (R) enantiomer of chlorine and fluorine, and wherein said opioid is morphine. 21. The use of claim 20, wherein said compound enhances the analgesic effect of morphine. 22. A process for producing the compound of claim 7, comprising (a) In the presence of a base, the azetidine having the formula 1' is made in an inert solvent wherein P is a nitrogen protecting group, L is an anionic leaving group selected from tosylate, mesylate, and triflate, reacted with a polysubstituted pyridyl compound having the following formula 2

;and (b) Remove P. 23. The process of claim 22, wherein removal of P by p-toluenesulfonic acid directly forms the p-toluenesulfonate salt. 24. The method of claim 22, wherein the stereochemistry of the 2-azetidine is (R). 25. The method of claim 22, wherein the stereochemistry of the 2-azetidine is (S). 26. The method of claim 22, further comprising adding an acid to the deprotected product to form a pharmaceutically acceptable salt. 27. The method of claim 22, wherein the azetidine is prepared by a method comprising (a) In the presence of a tertiary amine base, make D-aspartic acid or the corresponding ester O-R', wherein R' is selected from C ₁ -C ₆ alkyl, benzyl and substituted benzyl, and selected from Trialkylsilylating reagent reaction of trimethylsilyl chloride or tert-butyldimethylsilyl trifluoromethanesulfonate; (b) treating the product of step (a) with RMgX, wherein R is a C ₃ -C ₆ alkyl group with large steric hindrance; and X is chlorine, bromine or iodine; (c) cleavage of silyl moiety to form formula 7' compound wherein R' is here selected from H, C ₁ -C ₆ alkyl, benzyl and substituted benzyl, wherein the substituents are selected from commonly used aromatic substituents; (d) with being selected from diisobutylaluminum hydride, lithium aluminum hydride, one- or dihaloaluminum hydride, _AlH Reducing agent or the mixture reduction formula 7 ' compound of aluminum trichloride and lithium aluminum hydride, or with Reduction with a reducing agent selected from NaBH4, LiBH4 or CaBH4, followed by treatment with an aluminum hydride reducing agent; (e) protecting the azetidine nitrogen with a nitrogen protecting group P to form a compound of the formula, 28. The method of claim 22, wherein the azetidine is prepared by a method comprising (a) In the presence of a tertiary amine base, make L-aspartic acid or the corresponding ester O-R', wherein R' is selected from C ₁ -C ₆ alkyl, benzyl and substituted benzyl, and is selected from Trialkylsilylating reagent reaction of trimethylsilyl chloride or tert-butyldimethylsilyl trifluoromethanesulfonate; (b) treating the product of step (a) with RMgX, wherein R is a C ₃ -C ₆ alkyl group with large steric hindrance; and X is chlorine, bromine or iodine; (c) cleavage of silyl moieties to form formula 7" compound

wherein R' is here selected from H, C ₁ -C ₆ alkyl, benzyl and substituted benzyl, wherein the substituents are selected from commonly used aromatic substituents; (d) with being selected from diisobutylaluminum hydride, lithium aluminum hydride, one- or dihaloaluminum hydride, _AlH Reducing agent or the mixture reduction formula 7 " compound of aluminum trichloride and lithium aluminum hydride, or with Reduction with a reducing agent selected from NaBH4, LiBH4 or CaBH4, followed by treatment with an aluminum hydride reducing agent; (e) protecting the azetidine nitrogen with a nitrogen protecting group P to form a compound of the formula, 29. The method of claim 22, wherein the azetidine is prepared by a method comprising (a) In the presence of a tertiary amine base, make D-aspartic acid or the corresponding ester O-R', wherein R' is selected from C ₁ -C ₆ alkyl, benzyl and substituted benzyl, and selected from Trialkylsilylating reagent reaction of trimethylsilyl chloride or tert-butyldimethylsilyl trifluoromethanesulfonate; (b) treating the product of step (a) with RMgX, wherein R is a C ₃ -C ₆ alkyl group with large steric hindrance; and X is chlorine, bromine or iodine; (c) cleavage of silyl moiety to form formula 7' compound wherein R' is now selected from H, C ₁ -C ₆ alkyl, benzyl and substituted benzyl, wherein the substituents are selected from commonly used aromatic substituents; (d) reducing the compound of formula 7' by forming the corresponding thiolactam followed by reductive desulfurization; (e) protecting the azetidine nitrogen with a nitrogen protecting group P to form a compound of the formula,

30. The method of claim 22, wherein the azetidine is prepared by a method comprising (a) In the presence of a tertiary amine base, make L-aspartic acid or the corresponding ester O-R', wherein R' is selected from C ₁ -C ₆ alkyl, benzyl and substituted benzyl, and is selected from Trialkylsilylating reagent reaction of trimethylsilyl chloride or tert-butyldimethylsilyl trifluoromethanesulfonate; (b) treating the product of step (a) with RMgX, wherein R is a C ₃ -C ₆ alkyl group with large steric hindrance; and X is chlorine, bromine or iodine; (c) cleavage of silyl moieties to form formula 7" compound wherein R' is now selected from H, C ₁ -C ₆ alkyl, benzyl and substituted benzyl, wherein the substituents are selected from commonly used aromatic substituents; (d) reducing the compound of formula 7" by forming the corresponding thiolactam followed by reductive desulfurization; (e) protecting the azetidine nitrogen with a nitrogen protecting group P to form a compound of the formula,

31. Use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for controlling pain in mammals including humans

Wherein the stereochemical structure of Z, Y, X and 2-azetidine is selected from respectively: H, H, Me(S); H, H, Me(R); H, H, CN(S); H, H, Cl(S); H, H, Cl(R); H, H, Br(R); H, H, F(S); H, H, F (R); H, H, CHF ₂ (S); H, H, OMe(R); H, Me, Cl(S); H, Me, Cl(R); H, Et, F(S); H, Vinyl, Cl(S); H, Vinyl, Cl(R); H, Vinyl, F(S); H, Vinyl, F(R); H, ethynyl, Cl(S); H, ethynyl, Cl(R); H, Cl, Cl(S); H, Cl, Cl(R); H, Cl, F(S); H, Br, Me(S); H, Br, Me(R); H, Br, Cl(S); H, Br, Cl(R); H, Br, F(S); H, Br, F (R); H, Me, H(R); H, n-Pr, H(S); H, Vinyl, H(S); H, Vinyl, H(R); H, 3-propenyl, H(S); H, Cl, H(R); H, F, H(S); H, NO ₂ , H(S); H, OEt, H(S); Cl, H, H(S); Cl, H, H(R); F, H, H(S); F, H, F(S); F, H, Me(S); and F, H, Me(R); and wherein R together with the azetidine nitrogen forms a moiety selected from the group consisting of tertiary amines; amides; carbamates; ureas; enamines; selected from methyl, ethyl, isopropyl, n-propyl, isobutyl, tert-butyl, tert-amyl, n-pentyl, n-butyl, cyclohexylmethyl, 3-methyl-1-butyne- 3-yl, optional N-protected-Ala, optional N-protected-Phe, phthaloyl methyl ester, 4-diethylaminobenzoyl, 2-hydroxymethylbenzoyl ,Acetyl, tert-butoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, 4-methoxyphenoxycarbonyl, 4-carbonylmethoxyphenoxycarbonyl, 4-methyl Phenoxycarbonyl, 4-fluorophenoxycarbonyl, 4-chlorophenoxycarbonyl, 2,6-dimethylphenoxycarbonyl, 1-acetoxy-1-methyl-ethoxycarbonyl , Benzyloxycarbonyl, pyrrolidin-1-ylcarbonyl, where R' is H or Me,

Two of the azetidines are linked, N-succinimidomethyl and N-phthalimidomethyl. 32. The method of claim 31, wherein R and the azetidine nitrogen together form a moiety selected from the group consisting of: Tertiary amine; amides; carbamate; urea; Enamines; and Amidomethylamine. 33. The method of claim 31, wherein R is selected from the group consisting of: methyl, ethyl, isopropyl, n-propyl, isobutyl, t-butyl, t-amyl, n-pentyl, n-butyl, cyclohexylmethyl radical, 3-methyl-1 butyn-3-yl, optional N-protected-Ala, optional N-protected-Phe, phthaloyl methyl ester, 4-diethylaminobenzene Formyl, 2-hydroxymethylbenzoyl, acetyl, tert-butoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, 4-methoxyphenoxycarbonyl, 4-carbonylmethoxyphenoxycarbonyl, 4-methyl Phenoxycarbonyl, 4-fluorophenoxycarbonyl, 4-chlorophenoxycarbonyl, 2,6-dimethylphenoxycarbonyl, 1-acetoxy-1-methyl-ethoxycarbonyl , Benzyloxycarbonyl, pyrrolidin-1-ylcarbonyl,

where R' is H or Me,

Two of the azetidines are linked, N-succinimidomethyl and N-phthalimidomethyl. 34. A compound of formula I or a pharmaceutically acceptable salt thereof

Wherein the stereochemical structure of Z, Y, X and 2-azetidine is selected from respectively: H, H, Me(S); H, H, Me(R); H, H, CN(S); H, H, Cl(S); H, H, Cl(R); H, H, Br(R); H, H, F(S); H, H, F (R); H, H, CHF ₂ (S); H, H, OMe(R); H, Me, Cl(S); H, Me, Cl(R); H, Et, F(S); H, Vinyl, Cl(S); H, Vinyl, Cl(R); H, Vinyl, F(S); H, Vinyl, F(R); H, ethynyl, Cl(S); H, ethynyl, Cl(R); H, Cl, Cl(S); H, Cl, Cl(R); H, Clo, F(S); H, Br, Me(S); H, Br, Me(R); H, Br, Cl(S); H, Br, Cl(R); H, Br, F(S); H, Br, F (R); H, Me, H(R); H, n-Pr, H(S); H, Vinyl, H(S); H, Vinyl, H(R); H, 3-propenyl, H(S); H, Cl, H(R); H, F, H(S); H, NO ₂ , H(S); H, OEt, H(S); Cl, H, H(S); Cl, H, H(R); F, H, H(S); F, H, F(S); F, H, Me(S); and F, H, Me(R); and wherein R together with the azetidine nitrogen forms a moiety selected from the group consisting of tertiary amines; amides; carbamates; ureas; enamines; selected from methyl, ethyl, isopropyl, n-propyl, isobutyl, tert-butyl, tert-amyl, n-pentyl, n-butyl, cyclohexylmethyl, 3-methyl-1-butyne- 3-yl, optional N-protected-Ala, optional N-protected-Phe, phthaloyl methyl ester, 4-diethylaminobenzoyl, 2-hydroxymethylbenzoyl ,Acetyl, tert-butoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, 4-methoxyphenoxycarbonyl, 4-carbonylmethoxyphenoxycarbonyl, 4-methyl Phenoxycarbonyl, 4-fluorophenoxycarbonyl, 4-chlorophenoxycarbonyl, 2,6-dimethylphenoxycarbonyl, 1-acetoxy-1-methyl-ethoxycarbonyl , Benzyloxycarbonyl, pyrrolidin-1-ylcarbonyl, where R' is H or Me,

Two of the azetidines are linked, N-succinimidomethyl and N-phthalimidomethyl. 35. The compound of claim 34, wherein R together with the azetidine nitrogen forms a moiety selected from the group consisting of: Tertiary amine; amides; carbamate; urea; Enamines; and Amidomethylamine. 36. The compound of claim 34, wherein R is selected from the group consisting of: methyl, ethyl, isopropyl, n-propyl, isobutyl, tert-butyl, tert-amyl, n-pentyl, n-butyl, cyclohexylmethyl radical, 3-methyl-1 butyn-3-yl, optional N-protected-Ala, optional N-protected-Phe, phthaloyl methyl ester, 4-diethylaminobenzene Formyl, 2-hydroxymethylbenzoyl, acetyl,

tert-butoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, 4-methoxyphenoxycarbonyl, 4-carbonylmethoxyphenoxycarbonyl, 4-methyl Phenoxycarbonyl, 4-fluorophenoxycarbonyl, 4-chlorophenoxycarbonyl, 2,6-dimethylphenoxycarbonyl, 1-acetoxy-1-methyl-ethoxycarbonyl , Benzyloxycarbonyl, pyrrolidin-1-ylcarbonyl, where R' is H or Me,

Two of the azetidines are linked, N-succinimidomethyl and N-phthalimidomethyl.

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